here - Heinz Nixdorf-Lehrstuhl für Medizinische Elektronik

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Heinz Nixdorf-Lehrstuhl für Medizinische
Elektronik
Science Report 2002-2012
Table of contents
FOREWORD
7
SENSOR TECHNOLOGY
Microsensor system for measuring surface contamination - [KONTAMIN]
08
Biohybrid sensor system with living cells and electronic components [cellristor®]
10
ISFET (ion-sensitive field effect transistor) as a planar pH sensor on multiparametric cell chips
14
Selective coupling of cells by means of suitable materials, electrodes and layer structures for the
development of cell-based testing systems („cell-based“ assays)
18
Intelligent Multiwellplate
20
Development of methods for non-invasive measurement of blood glucose
24
Implantable wireless sensor system for monitoring bone healing
26
„PRINTS“ – Printed nanomaterials for microsensor technology
30
SYSTEMS
2
8
32
Silicon-algae hybrid sensor for remote monitoring of surface waters
32
Intelligent mobile lab for bioelectronic analytics [IMOLA]
34
Chips not mice: biohybrid microelectronic components, as an alternative to animal testing
36
Handheld system for mobile cell-based assays [µLA]
38
Virtual Lab – an interactive telemedicine system for personalised diagnosis and therapy
40
Non-invasive sensor technology for stress analysis as a means of maintaining mobility in the 50
plus generation – [FBA, (FahrerBeanspruchungsAnalyse) driver stress analysis]
42
Sensocopter: a flying multisensor platform
34
TUMOUR DIAGNOSTICS
46
Development of a patient-specific tumour chemosensitivity test based on a silicon sensor chip [CST]
46
Tumour micro-environment and tumour metabolism: systemic analysis using sensor chip technology
48
Automated high-throughput analysis platform for personalised cancer therapy [AHA]
50
Intelligent implant for tumour monitoring [IntelliTUM]
52
Closed-loop microsystem for tumour therapy [THEMIC]
54
THERAPY MODULES AND SYSTEMS
56
„Der Arzt im Gepäck“ (A doctor always at hand)
56
An intelligent splint for the diagnosis and treatment of teeth grinding
58
Tone and tonus
60
3
4
Enrichment and detection of molecules secreted by tumour cells using magnetic nanoparticles and
LC-MALDI-TOF mass spectroscopy
62
Cell transfection, targeting and positioning of agents marked with nanoparticles using static and
dynamic magnetic fields
64
Investigation of the inhibition of pathogen adhesion to intestinal cells caused by oligogalacturonic
acids (OGAs) using chip-based in vitro test systems
66
Isolation of human pancreatic islet cells and quality control: quality control and toxicological testing
of immunodepressants with chip-based test systems
68
Development and evaluation of a monitoring and treatment system for sleep-related breathing
disorders
72
Analysing the therapeutic relevance of the transmembrane potential of tumour cells using [EvoPot]
76
Multiparametric system for automated high-throughput analysis of nerve cells [neuroscreening]
80
Therapeutic magnetic stimulation
84
The „Lufttacho“: Sensors get wings
86
New therapeutic options with COMES®
88
KOMPASS - „Kognitives Medizinisches Personalisiertes Assistenzsystem” (Cognitive medical per
sonalised assistance system)
90
KoKeTT – the AAL test and training centre in cooperation with Hochschule Kempten
92
Development of a personalised pedal exerciser [PREAM - Prevention and Rehabilitation through
Activity and Motivation]
94
iBikos II - Development of a telematic rehabilitation exerciser as an integrated home care product
96
Diabetes management from a student‘s viewpoint – the project „DiaManTUM“
98
APPENDIX
100
Innovationszentrum – Spin-offs
100
Facilities
101
Faculty lectures, workshops and events
102
Honours and awards
104
List of researchers
106
Impressum
127
5
Foreword
The Heinz Nixdorf-Lehrstuhl für Medizinische Elektronik was founded in the year 2000 as a
joint venture between the Technische Universität München and the Heinz Nixdorf Stiftung
and has since then been chaired by Professor Dr. Bernhard Wolf.
Since the available facilities had previously been used for other purposes, extensive construction and renovation works were necessary, e.g. a biology clean room and instrumental
analysis systems were installed such as electron microscopy and analytical laboratories.
During the past ten years, various „lab-on-a-chip“ systems and so-called biohybrid components have been designed, produced and tested in our department. These components
combine microelectronic sensors with living cells and can be utilised as a new assay method for microphysiologic tests and monitoring in vitro and in vivo.
The research carried out at our department focuses on the implementation of biohybrid,
microsensor-based lab-on-chip systems designed for a screening of systemic agents and
for tumour diagnosis and therapy; it spans the development of sensor chips up to their
practical integration into the pharmaceutical and clinical environment. This research offers
direct insight into the complex dynamics of cellular reaction profiles under ambient physiological conditions.
Further research fields entail the development of intelligent microphysiological implants and
diagnostic and rehabilitative telemedicine. These research teams study systems which may
provide physicians and patients with new diagnostic and therapeutic options and concepts.
In addition, the novel systems are the basis for developing new products: this work is done
in cooperation with other faculties and with industrial partners in the fields of pharmaceutical drug discovery, medical diagnostics and environmental analysis.
In this context, the „Innovationszentrum Medizinische Elektronik e.V.“ (IME) has also become home to a group of innovative spin-off companies as well as a Steinbeis-Transferzentrum „Zell-Chip-Technologien”. Industrial project partners can avail themselves of the
expertise offered by „IME e.V.“.
This brochure gives a summary of the projects implemented during the past ten years.
All of the employees of the department would like to express their gratitude to the Heinz
Nixdorf Stiftung for its lasting support during the past years as well as the sustainable consulting of Dr. Horst Nasko. We also wish to thank the following funding institutions: Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Stiftung
Industrieforschung, as well as the Bayerische Forschungsstiftung, the Bund der Freunde
der Technischen Universität München e.V. and all the industrial partners concerned.
Munich, December 2012
7
Sensor Technology
Microsensor system for measuring surface contamination - [KONTAMIN]
The aim of KONTAMIN, a cooperative project funded by the Bundesministerium für Bildung und Forschung, was to develop a bacterial sensor to enable the electronic measurement of microbe contamination (e.g. on a butcher‘s meat counter).
So far, the standard method for determining surface contamination has entailed the use
of tests involving luminescence measurement. To this end, a defined wipe of the contaminated surface is used to collect a microbe sample which is then placed in a measurement
solution.
The results of the KONTAMIN project revealed that the electronic measurement of the
germ concentration in liquids is actually possible with relatively low germ content, provided that the germs can be accumulated in the direct vicinity of the sensor. This was
achieved by using a dielectrophoretic method. In an inhomogeneous electric field, forces
are exerted on polarisable microparticles – in this case the bacteria – that move the microbes towards the strongest field gradient. If adequately designed electrodes are used,
the bacteria thus accumulated will change the electric impedance of the sensor. Sensor
sensitivity can be
To determine the degree of contamination of a surface, a sensor suitable for use in a twostep measuring method was developed. The bacteria are first accumulated on the surface
of the sensor and then determined by measuring the sensor impedance variations caused
by the accumulated bacteria. The field distribution in the sensor structure was optimised
by means of numeric field computations. The sensor itself was manufactured using a photolithographic process well-known in semiconductor technology. A considerable sensitivity of 105 bacteria / ml has been achieved.
In principle, it is possible to further increase this sensitivity: on the one hand by utilising
nanoparticles with coupling properties for bacteria, and on the other hand by using a
larger liquid reservoir and by extending the bacterial accumulation stage accordingly.
Fig. 1: Left: multilayer sensor design for
a two-step measuring principle;
1
2
a). Accumulating the microbes by
3
4
means of dielectrophoresis (conductive
tracks 1, 2);
b) Measuring the impedance variation
(conductive tracks 1, 3 and 2, 4); Right:
final sensor structure on a glass substrate, in the form of a sandwich sensor.
glass substrate
8
isolation
Fig. 2: Bacteria / ml in de-ionised water
Publications
T. Weyh, K. Wendicke, B. Gleich, B. Wolf, „Optimisation of a Bacteria Sensitive Sensor“;in
2nd European Medical and Biological Engineering Conference,Vienna, December 2002.
IFMBE Proceedings Vol I, pp. 332 – 333.
T. Weyh, K. Wendicke, B. Wolf „Simulation and Design of a Bacteria Sensor“, Sensor 2003
Conference, Nuremberg, May 2003.
T. Weyh, B. Gleich, B. Wolf „Design of a Bacteria Sensitive Biosensor“;DECHEMA; Jahrestagung der Biotechnologen, Posterbeitrag, Munich-Garching, April 2003.
T. Weyh, K. Wendicke, B. Gleich, B. Wolf, „Empfindlichkeitssteigerung von Biosensoren zur
Bestim-mung von Bakterienkonzentrationen durch Mikropartikel“, 6. Dresdner Sensor-Symposium, Dresden, December 8-10, 2003. Dresdner Beiträge zur Sensorik (Tagungsband),
J.G. Baselt und G. Gerlach (Hg.), w.e.b. Universitätsverlag, Dresden 2003, pp. 239-242.
B. Gleich, „Chipgestützte Keimzählung in flüssigen Medien“, 6. Würzburger Medizintechnik
Kongress, May 10, 2005.
This research was funded by the Bundesministerium für Bildung und Forschung.
Project title: Kontamin; project life span: 2000 to 2003
9
Biohybrid sensor system with living cells and electronic components
[cellristor®]
In recent years, advances in microelectronics and biotechnology have facilitated the
development of stable constructs made of living cells combined with electronically active
components. In the cellristor® project, the biological signal response of cells is converted
into electronically readable signals (Fig. 1). Analogue to transistors (transfer resistors), this
type of biohybrid sensor system is defined as a cellristor®.
Fig. 1: Left: diagram of a cellristor®;
right: scanning electron microscope
(SEM) image of cells on a transistor
array in a tentative project.
There are multiple ways to achieve the physical basis for a cellristor® along with a wide variety of measuring principles. Film-type resistors, diodes, transistors (e.g. ISFETs), planar
capacitances and electrode systems from technical sensor structures can be utilised in
the same way as the corresponding components used in polymer electronics.
If living cells are used, it is also necessary to ensure appropriate living conditions. This
can be achieved by adequate design and connection technologies, and increasingly by
microsystem technology.
10
F ig. 2: Example of the technology in
practice
Fig. 2 illustrates an example of the technical implementation of a cellristor®. The sensor
chip comprises the physical sensors by which the signals of a living organism (e.g. an
animal cell, a yeast, an alga) are captured. A technical life support system provides a
micromilieu for the organism similar to the in-vivo situation.
Figure 3 illustrates the variation in the vitality parameters (pH und pO2) of green algae
Chlorella Kessleri used as biological part of the cellristor® in this case over time. A study
of the sensitivity to the herbicide Metramitron revealed the following findings: In the
characteristic signal curve, the amplitude changed after the toxic substance was added.
The measuring cycle revealed the metabolic activity of the algae to be decreased. In the
following measuring cycle, the culture medium had returned to a non-contaminated state
which again regenerated the cells.
The biosensor system described here, which uses living cells as signal converters, can be
used as a sensitive component in addition or alternative to existing measuring instruments
for environmental monitoring. Due to its low operational costs and by involving the mobile
radio network, it is possible to achieve a degree of flexibility that allows for extensive
detection of environmental parameters. The automatic analysis and evaluation of the
measured data permits rapid detection of environmental influencesor the occurrence of
unusual water pollution. By using living organisms, it is possible to respond to any type of
toxin which can otherwise only be selectively detected by means of elaborate chemical
methods.
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Fig. 3: Cell vitality parameters, pH
and pO2, measured from green algae
Chlorella Kessleri. After approx. 235
minutes, the herbicide Metamitron was
added and decreased cell metabolism
was detected. Regeneration of this
test organism can be observed after
removing the herbicide. These data
were generated in a joint research
project between our deparment and the
Limnologic Institute of the Technische
Universität München in Iffeldorf.
Publications
B. Wolf, Kraus, M. Brischwein, R. Ehret, W. Baumann, M. Lehmann, „Biofunctional hybrid
structures - cell-silicon hybrids for applications in biomedicine and bioinformatics“, Biochemistry and Bioenegetics vol. 46, pp. 215-225, 1998.
B. Wolf, H. Grothe, P. Friedrich, „Der emanzipierte Patient“, MEDengineering 2010, pp.
78 – 83.
T. Stadthagen: „Entwicklung eines online Gewässermonitoringssystems mittels Biosensorchips zum Nachweis ausgewählter Xenobiotika“, Dissertation, Technische Universität
München, 2007.
J. Wiest, M. Schmidhuber, D. Grundl, M. Brischwein, H. Grothe, B. Wolf: „Environmental
Engineering using Living Cells as Signal Transducers“, IEEE Africon 2007, Windhoek/Namibia, ISBN: 0-7803-8606-X, IEEE Catalog number: 04CH37590C.
This research was funded by the Heinz Nixdorf Stiftung and the company Erwin Quarder
Gruppe.Project title: Cellristor® (Cellristor® is a registered trademark of the Heinz NixdorfLehrstuhl für Medizinische Elektronik, Technische Universität München). Project life span:
2011 to 2012
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13
ISFET (ion-sensitive field effect transistor) as a planar pH sensor on multiparametric
cell chips
This project entailed the development of an NMOS technology process for manufacturing
multiparametric silicon sensor chips (Fig. 1), enabling the integration of all the sensors
needed for cytoscopy on one single chip.
Besides impedance and oxygen sensors, these include in particular ion-sensitive field
effect transistor structures (ISFET) serving as pH sensors. In these structures, the isolated,
unplated gate is activated by the ionic charges in the intracellular fluid above.
Fig. 1: Layout of the multiparametric silicon sensor chip and corresponding 4“
wafer. Besides the ISFETs for measuring
the pH, the sensor chip includes a Clark
sensor and O2-FETs for measuring
oxygen, as well as an impedance sensor (IDES) and a temperature sensitive
diode.
The manufacturing process is carried out as follows:
The starting material comprises p-doped, oxidised Si wafers (1). The source and drain areas of the FETs are defined by a photolithographic process and then etched (2) and doped
by means of an n-diffusion process (3).
The next step involves removal of the oxide ridge above the gate area (4) and formation
of the gate oxide. A silicon nitride layer acting as an ion-sensitive membrane is deposited
directly on the gate oxide (5).
The silicon dioxide layer deposited thereon (6) is only removed in the area of the source
and drain contacts (7), which are then metal-plated (8).
Two additional stress compensated silicon oxide/nitride passivation layers insulate the
sensors against short circuits in liquids (e.g. a cell culture medium) (9); and beyond that
they serve as an etching mask for exposing the ISFET gate area (10). Alternatively, a
photo-resist coating (SU-8) can also be applied for the purposes of passivation.
Fig. 3 shoes a microscopic image of a sensor chip with ISFETs overgrown by cells, Fig. 4.
gives an example of a tumour chemosensitivity experiment using these sensors.
14
Fig.2: Manufacturing process for the
sensor chip
Fig.3:C elll ayerg rowno n a sensor chip
ISFET‘s
Fig. 4 Reaction of LS174T-cells drugged
0,25
0,004
with CAA chemotherapeutic agent; the
acidification rate (changes of the pH
0,20
0,003
value in the cell culture medium) are
measured with two ISFETs (red and
yellow data points)
0,15
0,002
0,10
0,001
0,05
0,000
0,00
- 0,001
05
10
15
20
25
30
time [h]
15
Publications
B. Wolf, M. Brischwein, A.M. Otto, H.Grothe, „Microelectronics meets life sciences: Biohybrid microelectronic components for multiparametric lab-on-chip systems“, mstnews No.
1/02, pp. 37-38, 2002.
H. Grothe, M. Brischwein, A.M. Otto, E. Motrescu, C. Stepper, T. Henning, B. Wolf, „Bioelectronic chips and systems for life science applications“, 21. DECHEMA- Jahrestagung
der Biotechnologen, Techn. Univ. München, Garching, April 2-4 2003, in: Book of Abstracts V 87- 90, 2003.
M. Brischwein, H. Grothe, A.M. Otto, C. Stepper, E. Motrescu, T. Weyh, B. Wolf, „Living
Cells on Chip: Bioanalytical Applications“, in: Ultrathin Electrochemical Chemo- and Biosensors. Mirsky, V.M. (ed.), 159-180. Springer-Verlag, Berlin 2004.
B. Wolf, M. Brischwein, H. Grothe, C. Stepper, J. Ressler, T. Weyh, „Lab-on-a-chip Systems for Cellular Assays“, in: G. Urban (ed.), BioMEMS. Series: Microsystems, Vol. 16, pp.
269-308, Springer-Verlag, Dordrecht (NL) 2006, ISBN-10:0-387-28731-0, ISBN-13: 978-0387-28731-7.
This research was funded by the Heinz Nixdorf Stiftung.
Project title: „ISFET (ionensensitiver Feldeffekttransistor) als planarer pH-Sensor auf
multiparametrischen Zellchips“ (ISFET (ion-sensitive field effect transistor) as a planar pH
sensor on multiparametric cell chips) Project life span: 2001 to 2004
16
17
Selective coupling of cells by means of suitable materials, electrodes and layer
structures for the development of cell-based testing systems („cell-based“ assays)
By using cell-based testing systems, living cells and tissues can be analysed on bioelectronic sensor chips in an environment that is very similar to the in-vivo setting. In this
project, sensors detecting cellular metabolism from the acidification of the surrounding
medium (pH sensor) and the oxygen consumption of the cells within this medium (oxygen
sensor), were integrated on a chip. Cell adhesion is measured with impedance sensors,
and temperature is monitored with a thermal sensor.
To examine the influence of an agent, the variation rates in the pH and pO2 sensor signals
typical of normal cell metabolism are used as reference values. By adding a chemotherapeutic agent to a tumour cell sample taken from a cancer patient, for example, the
effectiveness of the applied drug can be evaluated. This is done by observing the change
in the acidification rates and the oxygen consumption of the tumour cells. This method
allows the potential effect of chemotherapy to be verified prior to starting treatment. Consequently, on the one hand the highly unpleasant side effects of chemotherapeutic drugs
can be reduced, and on the other hand treatment costs can be significantly decreased by
avoiding multiple courses of chemotherapy.
Among others, the pH sensor plays an important role in these measurements. A particular
focus of this project was to study the applicability of pH sensors that are simple to integrate on the sensor chip at low cost as a replacement for ISFETs. To this end, use is made
of the pH sensitivity of metal oxides, with RuO2 proving to be particularly suitable.
Fig. 1: Multiparametric sensor chips
for cellular assays; left: microscopable
glass chip with integrated sensors;
right: ceramic chip with the same
functionality
18
Fig. 1 depicts a multiparametric sensor chip on a transparent glass substrate that allows
visualization of cellular assysays using an inverted microscope, as well as a ceramic chip
with the same functionality, both developed in the course of this project.
The RuO2 sensor can be used over a wide pH range and reacts to pH variations within seconds.
Fig. 2: Output signal of the RuO2 sensor
Publications
upon a pH variation in the fluid
J. Ressler, J. Wiest, H. Grothe, M. Brischwein, T. Asmus, K. Wienand, B. Wolf, „CeramicBased Multi-Parametric Sensorchip For Cost-Effective Monitoring Of Living Cells Or Tissue“, IFMBE Proceedings Vol. 10, 2005, 7th International Conference on Cellular Engineering, pp. 37-4.1, 2005.
J. Wiest, M. Brischwein, J. Ressler, A.M. Otto, H. Grothe, B. Wolf, „Cellular Assays with
Multiparametric Bioelectronic Sensor Chips“ ,Chimia 59, pp. 243-246, 2005.
J. Ressler, H. Grothe, M. Brischwein, B. Wolf, „Low-cost biosensors: ceramic-based multiparametric sensorchip for functional screening“, Biomedizinische Technik Vol. 50, Supplementary vol. 1, Part 1, pp. 531-53, 2005.
J. Wiest, M. Schmidhuber, J. Ressler, A. Scholz, M. Brischwein, B. Wolf, „Cell Based
Assays For Diagnostic And Therapy On Multiparametric Biosensor Chips With An Intelligent Mobile Lab“, IFMBE Proceedings Vol. 10, 7th International Conference on Cellular
Engineering 2005, pp. 29-32, 2005.
J. Wiest, T. Stadthagen, M. Schmidhuber, M. Brischwein, J. Ressler, U. Raeder, H.
Grothe, A. Melzer, B. Wolf , „Intelligent Mobile Lab for Metabolics in Environmental Monitoring“, Analytical Letters, Vol. 39, Issue 8, Jul 2006, Pages 1759 - 1771, DOI
10.1080/00032710600714089, URL http://dx.doi.org/10.1080/00032710600714089.
J. Ressler, H. Grothe, M. Brischwein, B. Wolf, „Monitoring of Living Cells or Tissue: Multiparametric Sensorchips for High-Content Screening“, BMT 2006 – Gemeinsame Jahrestagung der Schweizeri-schen, Deutschen und Österreichischen Gesellschaft für Biomedizinische Technik - Proceedings, Zürich, 04.09-09.09 2006, ISSN 0939-4990.
This research was funded by the Stiftung Industrieforschung.
Project title: „Selektive Verknüpfung von Zelleigenschaften mittels geeigneter Werkstoffe,
Elektroden und Schichtaufbauten“ (Selective combination of cell properties by means of
suitable materials, electrodes and layer structures)
Project life span: 1 April 2004 to 31 March 2006
19
Fig. 1: Pipetting robot of the Intelligent
Microplate Reader
Intelligent Multiwellplate
Living cells and tissue samples respond to experimental influences (e.g. applied pharmaceutical drugs) by means of a highly complex intracellular signal network. Their
response may lead to cell division, metabolic activation or even to cell death. If cellular
specimens are cultured on a planar chip with appropriate sensors, such responses can be
monitored in real time and in a label-free way.
A research group at our department has developed an automated cell-chip platform, the
so called „Intelligent Microplate Reader” (IMR) for recording of multiple parameters in
parallel (see also chapter “Automated high- troughput analysis platform for personalized
cancer therapy - AHA”). The system permits to study the dynamic response behaviour of
cells to applied agents under realistic conditions ( see Fig.1 and 5 ).
The researchers working on the „Intelligent Multiwellplate“ project designed a microwell
plate with optochemical sensors for pH and dissolved oxygen, analysing metabolic signatures of the cells and electrochemical impedance sensors for the detection of cell morphologic alterations. A pipetting robot actuates a fluidic system for controlled supply of
the specimens with fresh culture media or the required drug solutions. The sensor-based
plate has 24 wells and consists of a glass bottom connected to the polymer corpus (Fig.
2) In the centre of each well an area is left free from sensors to allow for bright field and
fluorescence microscopy.
20
The cell and tissue samples are cultured directly in the sensor area of the well. In order to
measure rates of extracellular acidification and cellular oxygen consumption with a reasonable time resolution, microreaction chambers have to be created to reduce the volume
of surrounding cell culture medium. This is achieved by a cover lid confining a flat volume
of approximately 23 µl that is regularly exchanged according to the selected experimental
protocol. The pipetting tips of the robot have access to side vessels adjacent to the microreaction chamber of each well (Fig. 3). Small hydrostatic pressure differences emerging
by the action of the robot cause a controlled regeneration of the media inside the microvolumes.
Fig. 2: Triple-chamber sensor plate
21
Fig.3: Sensor-based Multiwellplate
Fig. 4: Pipetting robot exchanges media
in Multiwellplate
22
Fig.5: Intelligent Microplate Reader
in open state. The incubator contains
the pipetting robot, the sensor plate
with the impedance electronic and an
insertion with a digital microscope,
underneath. A work surface with the
notebook through which the device
is controlled, can be pulled out from
the base.
Publications
M. Brischwein, T. Geisler, V. Lob, J. Wiest, J. Ressler, B. Wolf, „Chip statt Maus: Microsensorarrays zur Chemikalienprüfung“. Nachrichten aus der Chemie, Vol. 54, pp. 115-120, February
2006.
T. Geisler, J. Ressler, H. Harz, B. Wolf, R. Uhl, „Automated Multiparametric Platform for
High-Content and High-Throughput Analytical Screening on Living Cells“, IEEE Transactions on automation science and engineering, Vol. 3, No. 2, pp.169-176, April 2006.
V. Lob, T. Geisler, M. Brischwein, R. Uhl, B. Wolf, „Automated live cell screening system
based on a 24-well microplate with integrated micro fluidics“, Medical and Biological Engineering and Computing, Vol. 45, Number 11, pp. 1023-1028, 2007.
This research was funded by the Bayerische Forschungsstiftung.
Project title: „Intelligente Multiwellplatte“ (Intelligent Multiwellplate)
Project life span: 1 August 2004 to 31 July 2007
23
Development of methods for non-invasive measurement of blood glucose
A lot of energy has been invested, and multiple studies performed in the field of „diabetes“
worldwide to create a more convenient way for patients to monitor their blood glucose levels. Modern „blood glucose test strips“ require only a few microlitres of blood taken from
less painful areas such as the arm or the thigh.
However, invasive methods with intermittent measurements are always associated with
poor or insufficient blood glucose monitoring, e.g. while resting at night or during physical
activities hyperglycaemic and hypoglycaemic episodes may go undetected. Furthermore, the invasive sampling of blood involves risks for the patient such as infections, nerve
damage and a general risk of non-compliance.
The challenge of finding a suitable non-invasive transdermal method of measurement lies
in the development of sensors with a high level of sensitivity and reliability which are able
to translate small variations in the blood glucose level into an easily detectable variation of
the monitoring signal, while accounting for the layers of tissue between the sensor and the
capillary system. A possible drawback is the influence the following factors may have on
the measurement results: sweat, pigmentation, texture and thickness of the skin, artefacts
caused by breathing or body movements, ambient temperature, contact pressure exerted
by the sensor, as well as the data acquisition time. Under ideal conditions, the blood glucose concentrations should be detected within less than five minutes in a range of 18-540
mg/dl at a magnitude of error under 5%.
Non-invasive sensors can be based on the following two principles: either a direct
concept based on chemical analysis of the glucose molecule, or an indirect method for
detecting the effect the blood glucose has on secondary values such as skin temperature
or pH variations.
During this research, a more or less novel approach to „multivariate blood glucose monitoring“ was investigated: the parallel analysis of several values correlated with blood
glucose which allows for significantly reduced artefacts in the prognosis of blood glucose
levels – without any negative effects on the patient‘s compliance. The multivariate analysis
is performed by using algorithms based on so-called „neuronal networks“. The resulting
prognosis of the blood glucose level is then compared with the values taken from the gold
standard of invasive measurement and entered in a „Clarke Error Grid“ (Fig. 1).
24
Publications
C. E. F. Amaral, M. Brischwein, B. Wolf, „Multiparameter techniques for non-invasive measurement of blood glucose“, Sensors and Actuators B 140, pp. 12-16, 2009.
C. E. F. Amaral, B.Wolf, „Current development in non-invasive glucose monitoring“, Medical Engineering & Physics, 2008, Vol. 30, Issue 5, pp. 541-549, 2008.
C. E. F. Amaral, M. Brischwein, B. Wolf, „Microsensors Chips for Measurement of Cellular
Parameters“, Sensor 2005–Nuremberg, B3, 2005.
C. E. F. Amaral, B. Wolf, „Cell-Electrode Interface in Bioimpedance applications“. 4th IEEE
Conference on Nanotechnology. Munich, August 16-19, 2004, IEEE Proceedings (CD,
ISBN:0-7803-8537-3).
This research was possible thanks to a scholarship C.F Amaral was granted by the
Deutscher Akademischer Austauschdienst and was also supported by the Heinz Nixdorf
Stiftung.
Project title: „Entwicklung von Methoden zur nicht-invasiven Blutzuckerbestimmung“ (Development of methods for non-invasive measurement of blood glucose)
Project life span: 2004 to 2007
Fig. 1: Clarke Error Grid as a graphical
representation of the multivariate analysis results. This method categorises the
measurement value obtained from the
device into five zones, A to E. Zone A
represents clinically correct values, the
other zones are for incorrect diagnoses
with varying degrees of risk potential.
25
Implantable wireless sensor system for monitoring bone healing
Bone healing has so far been monitored by diagnostic imaging methods such as X-ray,
CT and MRI, or surgical intervention. Clinical experience provides reference values for
determining the permitted degree of mechanical stress on implants, e.g. dental implants.
Continuous monitoring of bone healing by means of microelectronic implants would
enable physicians to individually control the healing time, the stress on the implant, the
timing of transplantation and removal of the material used for osteosynthesis. The data
continually acquired during this project are being used to better understand and study the
processes taking place during bone healing.
The project team has developed an independent, implantable wireless measuring system.
The aim is to record the healing progress by measuring oxygen saturation at the fracture
site and provide the physician with the information thus acquired. The implant system
comprises an electrochemical oxygen sensor, a microcontroller and wireless communications system, and is powered by a primary cell. The data on oxygen saturation are
acquired periodically and sent to an external receiver via a radio interface, which in turn
forwards the data via a radio or USB connection to an Internet database. The researchers
involved or the attending physician can then view the data in a web browser. The implant
is coated with a biocompatible material to protect it against external influences.
The system was implanted in a bone defect on the cranial calvarium in sheep as a means
of demonstrating the functionality of the implant system as well as the correct operation of the wireless communications system. During the experiment, the electrochemical
sensors revealed a strong drift due to increasing biofouling at the sensor, thereby causing
unsatisfactory long-term stability. These findings initiated the development of an in-vivo
calibration system for the oxygen sensor and an innovative membrane coating for the
sensor surface as parts of the follow-up project „IntelliTUM“ at Heinz Nixdorf-Lehrstuhl für
Medizinische Elektronik.
868 Mhz
Data
868 Mhz
Data
Control
Control
USB
SensoBiteBox
Fig. 1: Signal transmission link of a
telematic implant
26
Internet
Transmission
Computer
Internet
Web server
PC with
interface
Fig. 2: Implanting the monitoring system
in an animal model
27
Fig. 3: Internet-based evaluation of the
real-time measurement data obtained at
the animal research institute
Publications
M. Sattler, J. Clauss, M. Schmidhuber, J. Belsky, B. Wolf, „Implantable sensor system
for the moni-toring of bone healing“, In: Ratko Magjarevic, Olaf Dössel und Wolfgang C.
Schlegel (Hg.): IFMBE Proceedings. Berlin, Heidelberg: Springer Berlin Heidelberg, pp.
281–284, 2009.
This research was funded by the Internet Privatstiftung Austria, Denta Beauté Qualitätszirkel
Project title: „Implantierbares drahtloses Sensorsystem zum Monitoring der Knochenheilung“ (Im-plantable wireless sensor system for monitoring bone healing)
Project life span: 2007
28
29
„PRINTS“ – Printed nanomaterials for microsensor technology
The current PRINTS project aims to fabricate conductive tracks, sensors and actuators
from nano-materials by means of inkjet printing. The team is working on simplifying the
fabrication process and on maintaining or even enhancing the functionality of the sensors
in comparison to other production techniques.
The ability to print electrically conductive structures is an attractive alternative to conventional photolithography, especially since it requires neither expensive masks nor high-temperature or vacuum processes. It offers a fast and contactless fabrication method that is
suitable for flexible substrates and minimises material consumption. Polymer or nanoparticle solutions can be printed on various substrates to form conductive, semiconductive
and insulating structures.
The printable sensor technology investigated in this project entails both electrochemical
and optical sensors. Actuators in the form of electrodes are used to stimulate the cultivated neurons and muscle cells. Uses for the printable multiparametric sensor chips include
biomedicine and cell analysis, drinking water quality tests, as well as electrochemical gas
microsensor technology.
To this end, the sensor material, substrate and printing processes for various nanomaterials based on printable dispersions („inks“) need to be perfectly adapted to every application. The form and properties of the printed structures depend largely on the printing
parameters, the substrate surface and the viscosity of the solution, among other factors.
The printing process itself is performed by means of a glass capillary tube (see Fig. 1a)
which ejects the ink from a small orifice using shock waves generated precisely by a piezo
actuator. The process of generating and releasing a droplet is illustrated in Fig. 1b). Fig. 2
illustrates conductive line structures in the form of impedance sensors printed on foil.
Fig. 1: InkJet printing of nanomaterials;
a) The glass capillary tube used for printing (right) and camera for monitoring
the printed lines (middle); b) Release of
a droplet from the printing capillary
30
Publications
N. Mzoughi, H. Grothe, B. Wolf, P. Lugli, G. Scarpa, „pH-Empfindlichkeit biokompatibler
P3HT-OFETs“, Proceedings 5. Jahrestagung Ak BioMST, 6.5, June 23-24, 2009, Garching.
N. Mzoughi, H. Grothe, B. Wolf, P. Lugli, G. Scarpa, „pH-sensitive Schichten aus P3HT
und CNTs für Zell-Chip Sensoren“, 6. Jahrestagung Ak BioMST, Nov. 10-11, 2010, Sankt
Augustin, Fraunhofer FIT, Schloss Birlinghoven.
B. Neumann, N. Mzoughi, H. Grothe, B. Wolf, „Nanosensoren. Inkjet Printing of Nanomaterials for Microsensors“, Biomedizinische Technik/Biomedical Engineering, Vol. 56, No. s1,
pp. 1–8, ISSN 0013-5585, DOI: 10.1515/BMT.2011.819, September 2011.
N. Mzoughi, B. Neumann, H. Grothe, B. Wolf, „Sensorik Chemo/Bio. Inkjet printed electrodes on PET substrate for biosensing applications“, Biomedizinische Technik/Biomedical
Engineering, Vol. 56, No. s1, pp. 1–12, ISSN 0013-5585, DOI: 10.1515/BMT.2011.844,
September 2011.
N. Mzoughi, A. Abdellah, Q. Gong, H. Grothe, P. Lugli, B. Wolf, G. Scarpa, „Characterization of novel impedimetric pH-sensors based on solution-processable biocompatible
thin-film semiconducting organic coatings“, Submitted for publication at Sensors and
Actuators, 2012.
N. Mzoughi, Y. Eminaga, H. Grothe, B. Wolf, G. Scarpa, P. Lugli, „pH-Sensoren auf Basis
biokompatibler halbleitender Polymere“, In: Bernhard Wolf (Hg.): Bioelektronische Diagnose- und Therapiesysteme. m3: microelectronic meets medicine. 1. Aufl. 2012, Aachen:
Shaker Verlag, pp. 237–246. ISBN: 978-3-8440-0831-9.
This research was funded by the Bundesministerium für Bildung und Forschung
Project title: „PRINTS - Gedruckte Nanomaterialien für die Mikrosensorik“ (PRINTS – Printed nanoma-terials for microsensor technology),
Fig. 2: Impedance sensors printed on
foil for integration in cell-based assays
for diagnostic use
Systems
Silicon-algae hybrid sensor for remote monitoring of surface waters
Fig. 2: Floating autonomous support
unit suitable for various water monitoring sensors. The acquired data are
radio-transmitted to a central office. The
project group investigated how chipbased biomonitors may be integrated
into this type of support unit. (Joint
project with the company Rhode und
Schwarz GmbH, Munich)
Fig. 1: Diatoms colonised on a silicon
chip with ion-sensitive field-effect
transistors
Continuous monitoring of lakes, rivers or municipal and industrial water discharges is an
appropriate means of complying with European quality standards for surface water reservoirs. Further, such an approach enables water to be monitored for reasons of environmental protection.
Currently, only in isolated cases „environmental monitors“ (Umweltmonitore) are used
for water conservation purposes. This is done, for example by visually monitoring the
swimming behaviour of fish or water fleas. Usually, this kind of biomonitoring is achieved
by observing an „effect“ on a target organism, in contrast to determining the concentrations of certain substances as is the aim of chemical analysis. Currently, there are only
few publications on the investigation of portable cell-based testing systems for long-term
monitoring outside the lab.
This project, which was initiated in cooperation with a local dairy in the Ammersee region
near Munich, involved colonising monocellular green algae on silicon sensor chips. The
pH sensors on the silicon chip are able to measure changes in the microenvironment of
the algae which are permanently influenced by their own aerobic or photosynthetic metabolism. The resulting „biohybrid element“, comprising the living organism and solid state
sensors, permits detection of the synergistic effects of potential pollutants depending on
the respective sensitivity profile of the algae species used.
The sensor chip is the central component of the biomonitor system. Further components
are peripheral systems such as a controlled fluidic system with a filter unit for supplying
the water to be tested, an illumination system to allow photosynthesis, radio modules for
wireless data transmission, as well as a central electronic control unit. Since the complete system is designed to work independently between the servicing intervals (several
months), it is also important to ensure minimum energy consumption in all components.
Fig. 3 is an illustrative example of the water quality monitoring system and shows how
living algae on a sensor chip are used to monitor the quality of aquarium water. The algae
metabolism reacts even to low degrees of contamination in the test water, which is replaced in intervals of a few minutes. ISFETs measure the pH value directly under the algae.
The vitality of the algae, which is an important indicator of water quality, is analysed by
examining the pH variations.
32
Publications
J. Wiest, T. Stadthagen, M. Schmidhuber, M. Brischwein, J. Ressler, U. Raeder, H. Grothe,
„Intelligent Mobile Lab for Metabolics in Environmental Monitoring“, Analytical Letters, 39:
1759–1771, 2006.
T. Stadthagen, U. Raeder, J. Wiest, A. Melzer, B. Wolf, „Intelligent mobile Laboratory (IMOLA). Bio-monitoring mittels Biosensorchip-Technologie“, Jahrestagung 2006 der Gesellschaft für Limnologie e.V. (DGL) (2006, annual meeting of the DGL), p. 165, 2006.
Wiest, J, „Gewässerüberwachung mit biohybriden Sensorchips“, LaborPraxis, November
2008, pp.26-27, 2008.
Wiest, J., „Toxizitätstest mit Grünalgen als Testorganismus“, energie | wasser-praxis, 7+8,
2009, p.90, 2009.
This research was funded by Bayern Innovativ, the Andechser Molkerei Scheitz GmbH, as
well as the Rohde und Schwarz GmbH München.
Project life span: September 2001 to September 2002
In 2008, the department was awarded the E.ON Umweltpreis (E.ON environmental award)
for this work.
Fig. 3: Monitoring of water quality: (1)
Aquarium water inflow and outflow; (2)
Sensor module with pH-ISFETs, algae
culture on silicon sensor chips and LED
light source for ensuring photosynthesis; (3) Electronic unit for the pH-ISFETs
with data display.
33
Intelligent mobile lab for bioelectronic analytics [IMOLA]
The Intelligent Mobile Lab (IMOLA) provides information on the metabolism and morphology of living cells. This system is able to perform a label-free detection of cellular responses
to any experimental stimulation. The real time monitoring of cellular behavior is a key technology for the development of cell-based methods and therapies. The cellular specimens
are examined by measuring rates of extracellular acidification (pH), cellular respiration
(pO2) and variations in cellular morphology (modulating the electric impedance of electrodes). Extracellular acidification and cellular respiration provide insight into the metabolic
signature of the cell or tissue sample. Bioimpedance measurement provides information
about variations in proliferation and morphology.
Fig. 1: BioChip-C (side length: 24 mm)
with two pH sensors, two bioimpedance sensors, a sensor for measuring
dissolved oxygen, a temperature sensor
and various test electrodes.
Cells are cultivated directly on a „BioChip” comprising the electrochemical microsensors
for pH value, dissolved oxygen concentration and bioimpedance, plus an integrated temperature sensor for temperature control.
The BioChip as a self-contained cell culture vessel is placed into the IMOLA system and
connected to a closed fluidic system.
The software module DALiA (Data Acquisition and Link Application) supplied with the
IMOLA system serves for configuration and monitoring of ongoing experiments. It permits
the adjustment of experimental protocols. Additional features are the graphical display of
the measured data and a database for data storage.
When taking measurements from the cells, the driving pump is alternately switched on
and off. When in the „off“ position, the BioChips take measurements from the cellular
specimens on the chip surface. During the subsequent pump phase, the microsensors are
recalibrated and the cells are supplied with fresh cell culture medium or drug solutions.
The duration of continuous cell monitoring may be up to several days.
A variety of cell types have already been investigated on the IMOLA System, including
cells growing in suspension (e.g. yeasts and algae), adherent cell lines (e.g. MCF-7, L929,
HeLa), cell cultures prepared from primary human tissue or three-dimensional spheroids.
Fig. 2: The complete system
34
Key experiments have shown a potential for applications in individualised anticancer
chemotherapy, pharmaceutical drug development, regenerative medicine, alternatives to
animal testing and environmental monitoring. The spin-off cellasys GmbH (www.cellasys.
com) has further developed and commercialised the IMOLA technology.
Publications
J. Wiest, M. Brischwein, J. Ressler, A.M. Otto, H. Grothe, B. Wolf, „Cellular Assays with
Multiparametric Bioelectronic Sensor Chips“, Chimia, Vol. 59(5), pp. 243-246, 2005.
J. Wiest, T. Stadthagen, M. Schmidhuber, M. Brischwein, J. Ressler, U. Raeder, H. Grothe,
A. Melzer, B. Wolf, „Intelligent Mobile Lab for Metabolics in Environmental Monitoring“,
Analytical Letters, Vol. 39, 8, 1759-1771, DOI 10.1080/00032710600714089, 2006.
B. Wolf, M. Brischwein, V. Lob, J. Ressler, J.Wiest, „Cellular signaling: aspects for tumour
diagnosis and therapy“, Biomedizinische Technik, Vol. 52, pp. 164-168, DOI 10.1515/
BMT.2007.030, 2007.
J. Wiest, M. Brischwein, A.M. Otto, B. Wolf, „Cell based assay for label-free, multiparametric, long-term monitoring of cellular vitality“, ALTEX, 26, 96, ISSN 1868-596X, 2009.
M. Brischwein, H. Grothe, J. Wiest, M. Zottmann, J. Ressler, B. Wolf, „Planar Ruthenium
Oxide Sen-sors for Cell-on-a-chip Metabolic Studies“, Chemical Analysis (Warsaw), Vol.
54, pp.1193-1200, 2009.
J. Wiest, U. Schnakenberg, Ch. Koch, W. Wirths, F. Stadler, T. Bachinger, H. Grothe, B.
Wolf, „An Iridium-oxide pH sensor for cell based assays“, Biomed Tech , 56 (Suppl. 1) DOI
10.1515/BMT.2011.276, 2011.
Project life span: 1 December 2005 to 30 June 2006
Fig. 3: The 6xIMOLA-IVD device
enables examination of six cell samples
at the same time. For optimum temperature control, the system is integrated
into an incubator.
35
Chips not mice: biohybrid microelectronic components as an alternative to animal
testing
Today, animal testing is still the method of choice for many issues of pharmaceutical product development and toxicological research. Legislation in the European Union however
is increasingly restrictive towards use of animals for biological or medical testing, mainly
due to ethical reasons.
Targeted effects and side reactions of new pharmaceutical compounds are to be tested
thoroughly prior to the launch of clinical trials with humans. Numerous other chemicals, which are brought into the environment need to be evaluated with respect to their
toxicology. Although it appears to be difficult to replace animal testing – with its distinct
capability to map complex inter-organ relationships and pharmacodynamics – completely,
their number can be reduced by the application of appropriate in-vitro alternatives based
on well-differentiated cells from human origin. Sensor-based and label-free cell assays
allow a continuous recording of cell responses to applied compounds in time scale from
minutes to many days, including the possibility to test recovery effects [1, 2].
There are various approaches to such biohybrid devices comprising cellular target and
microscaled sensing elements. We selected sensor chips based on glass, ceramic and
silicon substrate integrating sensors for pH value, dissolved oxygen value and electric
impedance (Fig. 1). Cells or tissues are directly cultured on the surface of these sensor
chips.
Necessary additional components to arrive at practical instruments are cell culture maintenance systems including fluidics for regular exchange of culture media or drug solutions
and devices for temperature control. In general it is important to strictly keep stress-free
environmental conditions resembling the physiological in-vivo situation as close as possible.
As in the world of technology, these systems may be regarded as „test benches“ for living
cells or tissue enabling the observation of both rapid, acute and cytotoxic effects and slo-
wer, chronic or cytostatic responses of cells to nearly any applied chemical compound [3, 4].
Publications
[1] D. Weiss, H. Grothe, B. Wolf and J. Wiest, “BioChip-based Electrochemical Platform for
the Label-free Monitoring of Living Cells”, ATLA 40, p. 35, 2012.
[2] J. Wiest, “Extracellular acidification and changes in bioimpedance of L929 cells”, ALTEX 28, p. 76, 2011.
[3] M. Brischwein, E.R. Motrescu, A.M. Otto, E. Cabala, H.Grothe, B. Wolf, „Functional
Cellular Assays with Multiparametric Silicon Sensor Chips“, Lab on a Chip 3, pp. 234-240,
2003.
[4] M. Brischwein, H. Grothe, A.M. Otto, B. Wolf, „Microphysiological Testing of Tumor
Cells for Chemosensitivity: Use of Bioelectronic Sensor Chips“, mstnews 1, pp. 34-36,
2004.
This research was funded by the BMBF, the Heinz-Nixdorf-Stiftung, Bayern Innovativ and
the Bund der Freunde der Technischen Universität München e.V., as well as the Softwarehaus Zuleger GmbH.
Project title: „CHIP STATT MAUS: Planare und miniaturisierte mikroelektronische Sauerstoff-Sensoren für Tumor – Chemosensitivitätsanalysen“ (CHIPS NOT MICE: Planar and
miniaturised microelectronic oxygen sensors for tumour chemosensitivity analyses.)
Project life span: 2006
Fig. 1: Glass-, ceramic- and silicon sensor chips for cell and tissue analytics.
The circle indicates the cell culturing
surface
ISFET
37
Handheld system for mobile cell-based assays [µLA]
In recent years there have been an increasing number of reports about food contaminated with pesticides. While parts of this increase may be attributed to improved analytical
methods, these findings have generally sensitized the public for food quality. Currently
foodstuffs can only be analysed in time-consuming, costly tests in specialized laboratories. Novel testing devices such as the µLA (microLab) have been developed by a project
group in our department as a first step towards food analyses to be performed on site
with a handheld device that is easy to operate. An existing table-top version (IMOLA) was
the basis for successfully miniaturising the system, resulting in a wireless handheld device
for measuring the vitality of living cells.
Contaminated samples are placed on test cells in the system. If their vital state deteriorates, the system will detect this change, compare the values detected with reference values
in an Internet database via a wireless connection, and display the result for the user. This
research project employed an initial, miniaturised prototype with the name „μLA“ (micro
Lab) to perform a pivotal food testing experiment. The influence of conventional sprays
(fungicides) used in fruit farming on the vitality of yeast cells was examined, revealing that
the lowest concentration as recommended by the manufacturer affected cell vitality.
This is a big step toward providing a handheld system for analysis of food quality. For the
first time, there was evidence that living cells can be used as signal transducers for food
tests.
Figures 2 and 3 provide an illustrative example: „energy drinks“ were added to a test culture of yeast cells (Bioavailability-Test / “Bioverfügbarkeits-Test”).
Fig.1: μLA Handheld Biosensor system
for mobile cytobiologic assays and
cellristor-application.
38
Fig. 2: Energy drink A was added to
the yeast „Vita Vegan“. As a result,
the metabolism values increased substantially. After about 5h, the „energy
drink“ medium was replaced by the
initially used medium. Analysis method:
gradient analysis of the pH value and
pH1 rate
pH2 rate
Oxygen consumption rate
Polynominal (pH1 rate)
Polynominal (pH2 rate)
Polynominal (Oxygen consumption rate)
Publications
M. Schmidhuber, J. Bähr, J. Wiest, B. Wolf, „Ein mobiler Biosensor mit lebenden Zellen
zur Detektion von Pestiziden in Obst“. In B. Wolf (Hrsg.) Bioelektronische Diagnose- und
Therapiesysteme – m³: microelectronic meets medicine, Aachen, Shaker Verlag 2012, pp.
267-277, ISBN: 978-3-8440-0831-9.
M. Schmidhuber, J. Wiest, A.M. Otto, M. Brischwein, H. Grothe, B. Wolf, „Microelectronic
Cellular Vitality Monitoring“. In Noll, T. (ed.), Cells and Culture, ESACT Proceedings, Volume 4, Part 2, 2010, 89-93, DOI: 10.1007/978-90-481-3419-9_15.
partial oxygen pressure in the surrounding micromilieu.
Fig. 3: Energy drink B was added to
the yeast „Vita Vegan“. The metabolic
values did not increase as much as
with energy drink A. After about 5h, the
„energy drink“ medium was replaced
by the initially used medium. Analysis
method: gradient analysis of the pH
value and partial oxygen pressure in the
surrounding micromilieu.
M. Schmidhuber, J. Bähr, M. Zottmann, Y. Eminaga, J. Wiest, B. Wolf, „A mobile biosensor
using living cells for detection of pesticide contamination in fruit“, Proceedings 20th Anniversary World Con-gress on Biosensors, May 26-28, 2010, Glasgow, UK.
M. Schmidhuber, J. Wiest, and B. Wolf, „A mobile biosensor using living cells for water
quality analy-sis“, WC 2009, IFMBE Proceedings 25/VIII, pp. 24–26.
M. Schmidhuber, B. Becker, J. Wiest, B. Wolf, „Development of a Multiparametric Handheld Biosensor for use in Mobile Applications“, The IEEE Region 8 Eurocon 2009 Conference, May 18-23, 2009, Saint-Petersburg, Russia, ISBN 978-1-4244-3861-7, pp.
114-121, IEEE Catalog Number CFP09EUR-CDR 2009 IEEE, Library of Congress Number
2009900519.
M.Schmidhuber, J. Wiest, B. Wolf, „A Multiparametric Handheld Biosensor for Mobile
Metabolomics“, The IET Conference on Synthetic Biology, Systems Biology and Bioinformatics, March 23-25, 2009, Cambridge, UK, pp. 192-193.
Project title: „IMOLA - Intelligent Mobile Lab“
Project life span: 1 April 2006 to 31 March 2009
39
Virtual Lab – an interactive telemedicine system for personalised diagnosis and
therapy
When treating chronic diseases such as hypertension, diabetes mellitus, obesity or
respiratory disorders, a change in the patient‘s habits and lifestyle is usually the key to
sustainable therapeutic success. Such patients need long-term assistance and individual
coaching.
In this context, telemedical assistance systems can help to save resources and provide a
personalised solution. Our COMES® system (see article New therapy options with „COMES®“) offers a flexible concept involving a monitoring of body functions and therapeutical recommendations.
The virtual telemedicine lab as implemented with COMES® includes a large variety of options for use in diagnostics and therapy. Individual data patterns can be recorded from the
patient’s real-life environment using various sensor-based measuring devices with feedback and evaluation options. The Virtual Lab is an ideal development and test platform for
personalised treatment as well as for other therapeutic concepts.
The measurement of various parameters such as blood pressure, blood glucose or activity
allows both the patient and the attending medical professional to give direct behavioral
feedback. The efficiency of therapeutic interventions or recommended relaxation exercises in an authentic setting can be controlled immediately. Pharmaceutical interventions
and behavioural therapies may be tested under realistic conditions.
Fig. 1: The structure and principle of the
Virtual Lab
40
The system is particularly suitable for assisting the patient during therapy. This has been
demonstrated, for example, in preclinical research studies of bioacoustic hypertension
therapy. In particular, by using pieces of music chosen to suit the individual patient, we
used the anti-hypertensive effect of selected iterative sound patterns as a possible intervention in patients suffering from essential hypertension. This means that acoustic signals
can modulate metabolic and central nervous functions and evoke physiological effects in
humans. We also intend to investigate the described effects of different light qualities on
humans as a future extension of the Virtual Lab.
Fig. 2: The first generation of the
measuring devices connected to COMES© to be used as Virtual Lab equipment: 1) blood glucose meter; 2) wrist
sphygmomanometer; 3) Blackberry
telephone with Bluetooth connection; 4)
step counter; 5) upper arm sphygmomanometer
Publications
P. Friedrich, „Etablierung einer telemedizinisch gestützten bioakustischen Hypertonie-Therapie mittels Virtual Lab“, Dissertation, Heinz Nixdorf-Lehrstuhl für Medizinische Elektronik,
Technische Universität München, 2010.
P. Friedrich, T. Spittler, S. Tübinger, W. Tiedge, B. Wolf, „Comes® - ein Konzept zur personalisierten telemedizinischen Assistenz - oder - auf Anruf Arzt“, in e-Health 2011 Informationstechnologien und Telematik im Gesundheitswesen / Frank Duesberg (Ed.) Solingen,
Medical Future Verlag, 2010.
The Virtual Lab is the result of the research performed as part of various telemedicine projects
between 2005 and 2010, which was funded by the Heinz Nixdorf Stiftung and the Siemens AG.
41
Non-invasive sensor technology for stress analysis as a means of maintaining mobility in the 50 plus generation – [FBA, (FahrerBeanspruchungsAnalyse) driver stress
analysis]
Mobile individuals are socially more active and are found to be in better health. As for
other generations in our society, it is very important that the fastest growing age group,
namely those over 65 years of age, maintain their mobility.
In the future, the so-called „50 plus generation“ will increasingly outweigh other age
groups as drivers of personal vehicles. Potential driver assistance systems should therefore include an additional driver monitoring function. Such systems would provide individual
support adapted to the situation according to the driver‘s stress level: by means of a noninvasive sensor system, vital parameters could be measured and the stress level could be
calculated from physical, emotional and mental stress factors. The stress level data thus
obtained could be used to configure the driver assistance and emergency assistance systems.
In this context, our fdepartment has developed a system for analysing a driver‘s stress level by means of a mobile platform. This unit also records the vital parameters that enable
the assessment of cardiac irregularities, derived from ECG sensors integrated in the seat
or the steering wheel of the vehicle. If this system for „driver stress analysis and emergency detection“ is incorporated into the electronic system of a vehicle, it is possible to offer
support and assistance to the user.
The FBA system consists of four main components: Data acquisition from one or several
vital parameter data streams is complemented by an input feature for the required configuration. The central feature of this application is the driver stress analysis unit performing the evaluation. All stress levels calculated by the system as well as stress trends are
displayed on a special screen. As far as possible, these parameters are transmitted to the
vehicle assistance systems in order to generate the support and assistance described
above, thereby closing the feedback patch (see Fig. 1). The options provided by the database include trend analyses and long-term monitoring as well as a self-learning configuration feature.
The driver test bench developed in this project enables ECG data to be captured by goldplated copper electrodes integrated in the steering wheel. A monitoring amplifier is placed
directly in the steering wheel, with all further electronic processing equipment integrated in
a central board where all the parameters are digitalised by a data acquisition and measuring card with real-time capabilities. Data reduction and analysis of the measured values is
then performed synchronously by MATLAB/Simulink software in a mobile computer.
By selecting specific filters and processing steps, the stress level can be calculated and
retrieved by external applications. The graphics display can be seen in Fig. 3.
The system was incorporated into a passenger car and was successfully tested in urban
traffic.
42
Publications
Zauner, P.; Wolf, B.: „Der Autofahrer der Generation Plus“. München 2007.
This research was carried out in 2007 for the purposes of a dissertation on the topic
„Fahrerbeanspruchungsanalyse und Notfallerkennung mittels biomedizinischer Vitalparameter“ (Driver stress analysis and emergency detection by means of vital biomedical
parameters), in the context of a project initiated by Ambient Assisted Living (AAL).
Fig. 1: Driver stress analysis concept
Fig. 2: User screen of the FBA
Fig. 3: System test set-up
43
Sensocopter: a flying multisensor platform
Sensocopters are flying objects belonging to the helicopter family generating lift via four
propellers arranged in one plane. By tilting the propeller plane, quadrocopters are able to
move freely in all directions. In recent years, scientists have not only been interested in
sensocopters due to their agility but also because of the wide range ofpossibilities they
offer for unmanned aviation, irrespective of the fact that engineers have not yet been successful – or not sufficiently so – in developing these aircrafts for manned aviation.
There have been more and more media reports about the most recent scientific achievements in this field. Powerful video systems enable monitoring applications at minimum
effort and cost. By combining the copters with GPS or other tracking methods, their range
of application can be extended without needing to consider the RC pilot‘s range of vision.
Sensocopters equipped with appropriate sensor and control systems could be used in
areas that are virtually inaccessible to humans or pose a substantial risk to the pilot‘s
health. The drones may be able to detect contamination of all kinds, thus enabling their
extent and the associated risks to be assessed.
The sensocopter used at the Heinz Nixdorf-Lehrstuhl für Medizinische Elektronik is able
to fly on GPS-tracked routes and transmit images from an on-board camera to a mobile
ground station via radio. Via a Bluetooth interface, the data acquired by the on-board
sen-sors (gyroscope, acceleration sensors and altimeter) as well as the GPS position can
also be displayed at the mobile ground station. It is this same interface that can be used
to send pre-defined GPS routes to the sensocopter, which will then start to fly along these
routes when activated by remote control.
With the help of the integrated sensors (gas sensors, radioactivity, image sensors, chemical sensors), such a system permits an initial impression to be obtained of the situation
on the ground, thereby enabling the acquisition of various environmental and situational
parameters related to fires, disasters or other incidents without risking the health of emergency workers.
Currently, further interfaces and sensors are being tested to enhance and extend the range of obtainable data and enable better assessment of potential uses.
This research was carried out during the advanced university seminar „Quadrokopter: Eine
fliegende Plattform für Sensoranwendungen“ (Quadrocopter: a flying platform for sensor
applications) in the winter term of 2011.
44
Fig. 1: The sensocopter in starting position, with sensor interface and camera
Fig. 2: Wiring of the sensocopte
45
Tumour diagnostics
Development of a patient-specific tumour chemosensitivity test based on a silicon
sensor chip [CST]
Despite the advances that have been made in the field of chemotherapeutic drugs, patients still only receive certain therapies (known as the „stratification of patient groups“)
on the basis of little or relatively vague individual diagnostic data. It is general knowledge
that patients suffering from tumours of the same histopathologic class may respond very
differently to medication.
Our „chemo-sensitivity-testing” (CST) project saw the development of planar siliconbased sensor chips as a culture substrate of human tumour cells. The integrated sensors
record the functional cell reaction to agents that are applied to the chips. Specifically,
these sensors measure electrical impedance (Fig. 1), the dissolved oxygen concentration
and extracellular pH value.
This multiparametric approach increases testing safety and facilitates data interpretation.
The fact that this system does not require the cells on the chip to be marked in any way
allows for several days of continuous monitoring, a period necessary also for detecting
delayed cell reactions or potential recovery effects.
The measurement parameters are values that are closely interrelated with the cellular signal network: cell death for example is regularly coupled with cytomorphological changes
that are reflected by the electrical impedance values.
As a result of this project, we developed a six-channel device (Fig. 2) in cooperation with
our clinical and industrial partners. This device forms the basis for further developments
using clinical samples such as tissue collected during surgical interventions or exploratory
excisions (biopsies).
Fig.1: (Left) Layout of the silicon sensor
chip for measurements from the cell
cultures. Within the indicated area,
with a diameter of 6 mm (identified by
the two vertical lines), there are planar
sensors that are in direct contact with
the cells and the cell culture medium.
(Right) Section of a silicon sensor
chip with an interdigitated electrode
structure for electrical impedance measurements. A culture of LS 174 T cells
derived from human colon carcinoma is
growing on the surface. The right upper
window provides a detailed view at
higher magnification.
46
The company Bionas GmbH, a spin-off founded in cooperation with Micronas GmbH
introduced a follow-up model of that system into the market (www.bionas.de).
Fig. 2: Left: six-channel testing device.
Right: sensor chip with „Package“
and a fluidics adapter (white) on an
electronic socket
Publications
M. Brischwein, E.R. Motrescu, A. M. Otto, E. Cabala, H. Grothe, B. Wolf, „Functional Cellular Assays with Multiparametric Silicon Sensor Chips“, Lab on a Chip 3 (4), pp. 234-240,
LabChip 2003.
A.M. Otto, M. Brischwein, E. Motrescu, B. Wolf, „Analysis of drug action on tumour cell
metabolism using electronic sensor chips“, Archiv der Pharmazie 337, 682-686 2004.
E.R. Motrescu, A.M. Otto, M. Brischwein, S. Zahler, B. Wolf, „Dynamic analysis of metabolic effects of chloroacetaldehyde and cytochalasin B on tumour cells using bioelectronic
sensor chips“. J. Can. Res. Clin. Oncol. 131 (2005), 683-691 DOI 10.1007/s00432-0050015-2
Project title: „Entwicklung und Erprobung eines patientenspezifischen Tumour-Chemosensitivitäts-Assays auf der Basis eines Silizium-Sensor-Chips“ (Development and testing of a
patient-specific tumour chemosensitivity test based on a silicon sensor chip)
Project life span: November 2000 to June 2004
47
Tumour micro-environment and tumour metabolism: systemic analysis using sensor
chip technology
To understand the regulatory mechanisms of the energy metabolism, proliferation and
cytolysis of tumour cells, it is essential to learn about the characteristics of the microenvironment of tumour tissues. The microenvironment of a tumour cell encompasses not
only the surrounding cells and the so-called extracellular matrix, but more importantly the
soluble compartment containing growth factors, cytokines, nutrients and waste products,
and ions. The interplay between the micro-environment and the metabolic activity of a cell
or a cell population may provide diagnostic and prognostic indicators of cancer growth as
well as information useful for developing more efficient (chemo) therapeutic strategies
Fig. 1: Soluble substances in the
tumour micro-environment. Hypoxia
represents an insufficient oxygen level
in the tumour tissue. At the same time,
the milieu exhibits a low pH, excessive
The aim of the project entitled „Cell-based assays using bioelectronic sensor chips for the
dynamic analysis of tumour cell metabolism and chemosensitivity“ was to systematically
analyse basic metabolic parameters in tumour cell cultures by selecting predefined conditions representing different tumour microenvironments (Fig. 1)
lactic acid (lactate) and low concentrations of nutrients such as glutamine
and glucose. The interrelationships of
these values regulate the metabolic
patterns of the cells and also affect their
sensitivity to therapeutic measures.
48
Two well-characterised human breast cancer cell lines serve as a model for tumours of differing malignancy: Characteristic of one of these cell lines is the preservation of hormonal
sensitivities and cell contacts and low metastatic potential (MCF-7), while the other has
lost these differentiated functions and has a high metastatic potential (MDA-MB231). To
modulate their metabolism, the tumour cells are cultivated under predefined conditions as
outlined in Fig. 1. For clinical use, certain inhibitors of specific paths of energy metabolism
are tested for their efficacy under different microenvironmental conditions.
Our methodical approach comprises a defined number of different assay systems. These
include established biochemical and cytobiological assays for measuring specific cellular
activities. Using a newly developed technology based on multiparametric microsensor
chips on which cells are cultivated directly, rapid changes in pH and oxygen concentrations (closely associated with cellular metabolic activity) as well as in the electrical cellsubstrate impedance (changes in which are linked with the morphological parameters of
the cells) can be monitored in real-time. Using a fluidic perfusion system, it is furthermore
possible to not only simulate pre-defined microphysiological conditions, but also to maintain culture conditions for long-term incubation studies.
The results demonstrate, for example, that by combining extracellular glutamine and glucose levels with different pH values the said parameters interact in a non-linear fashion
with the energy metabolism – but do not correlate with the cell proliferation rate.
During our investigations, we obtained data suitable for describing the systems biology
of tumour cell metabolism in interaction with the tumour microenvironment. Moreover, it
is our aim to use this data to develop new options for efficient diagnostic and therapeutic
concepts in oncology.
Publications
A.M. Otto, M. Brischwein, E.R. Motrescu, B. Wolf, „Analysis of drug action on tumour cell
metabolism using electronic sensor chips“, Archiv der Pharmazie , Vol.337, pp. 682-686,
2004.
E.R. Motrescu, A.M. Otto, M. Brischwein, S. Zahler, B. Wolf, „Dynamic analysis of metabolic effects of chloroacetaldehyde and cytochalasin B on tumour cells using bioelectronic
sensor chips“, J. Can. Res. Clin. Oncol. Vol. 131, pp. 683-691 DOI 10.1007/s00432-0050015-2, 2005.
This research was funded by the Deutsche Forschungsgesellschaft.
Project title: „Cell-based assays using bioelectronic sensor chips for dynamic analysis of
tumour cell metabolism and chemosensitivity“
Project life span: 1 March to 28 February 2007
Fig. 2: Diagram of mitogenetic signal
transfer in a cell
49
Automated high-throughput analysis platform for personalised cancer therapy [AHA]
Personalised cancer chemotherapy depends on reliable assay methods, based either on
so-called „predictive biomarkers“ or on the direct functional assessment of the tumour
cells. While the first strategy is designed to indirectly associate molecular profiles with a
certain therapeutic response, the latter is aimed at directly assessing cellular chemosensitivity. The aim of the AHA project was to evaluate the chances of success with either
approach.
As a step in this direction, we developed a new assay platform using innovative technologies (Figs. 1, 2). This platform analyses the response of explanted human tumour tissue
(the project focused on breast cancer) in real time and without any marking steps. If data
on cell metabolism are used, it is possible to determine whether or not significant chemosensitivity exists. It is also possible to derive molecular parameters from treated and untreated samples, though there has been no evidence so far to show whether this information
has any predictive value.
The assay protocol focused in particular on defining the preparation process of the tissue
samples: from the conditions for explanting the tissue and its transport to the lab (as fast
as possible), to the clearly defined preparation routine. The variability of every single step
must be kept at a minimum when it comes to testing.
For the preparation protocol, thin, vital tissue slices obtained with a vibratome proved to
be well suited for the breast cancer tissue samples, since this method reduces the manipulative impact on the three-dimensional tissue structure to a minimum.
The test itself is performed mainly in an automated manner on a 24-well assay plate. The
normal duration of short-time culture and testing of the tissue samples is 96 hours, and an
agent is added after 24 hours.
Fig. 1. Left: assay platform, indicating
the position of the sensor plate (A), the
pipetting head (B), the storage ves-sels
(C) and the process microscope (D).
Right: section of breast cancer tissue in
the sensor plate. A nylon mesh facilitates sample transfer and enhances the
mass transfer between the sample and
the sensors.
50
Fig. 2: 24-well sensor plate with cover
(A). Top view of a well (B) with optical
sensors integrated in the base for
measuring the pH value (pH) and the
concentration of dissolved oxygen
(pO2) in the culture medium. Interdigitated electron structures (IE) enable cell
impedance to be recorded. Longitudinal
section of a well (C). By placing the
cover on the 24-well plate, the volume
of the culture medium is reduced (D),
forming a microreaction chamber
(MR). The medium exchange in the cell
Publications
R. Kleinhans, F. Demmel, B. Becker, T. Schwarzenberger, M. Brischwein, A. M. Otto, P.
Wolf, B. Wolf, „Real-time screening of the chemosensitivity of human tumour slices to
chemotherapeutical drug treatment“, European Journal of Cell Biology, p.55, Vol. 89S1,
Suppl. 60, ISSN 0171-9335, Elsevier, 33. Annual meeting of the DGZ, Regensburg 2010.
M. Zottmann, F. Demmel, B. Becker, R. Kleinhans, M. Brischwein, B. Wolf, „Multiparametric real time assay of cellular drug response: kinetics of cell metabolism and proliferation“,
34. Jahrestagung der Deutschen Gesellschaft für Zellbiologie, March 30 - April 2, 2011,
Bonn, p.75, 2011.
R. Kleinhans, F. Demmel, B. Becker, T. Schwarzenberger, M. Brischwein, P. Wolf, B. Wolf,
„Personalisierte Medizintechnik (2). Real-time screening of the chemosensitivity of human
tumour slices to chemotherapeutical drug treatment“, Biomedizinische Technik/Biomedical
Engineering, Volume 56, No. s1, pp. 1–6, ISSN 0013-5585, DOI: 10.1515/BMT.2011.834,
September 2011.
culture area results from the pipetting
process and is achieved by hydro-static
pressure compensation between the
interconnected chambers (E).
Fig. 3: Measuring the chemosensitivity
of a human mammary carcinoma tissue
sample. Adding the metabolite chloracetaldehyde (CAA, formed from ifosfamide or cyclophosphamide) results in a
substantial decrease of the acidification
activity and oxygen consumption in
this sample, while only little effect of doxorubicin can be seen here. By means
of statistical tests including controls,
it is possible to assess the degree of
sensitivity that must be expected and to
personalise the therapy for this patient
accordingly.
R. Kleinhans, M. Brischwein, P. Wang, B. Becker, F. Demmel, T. Schwarzenberger, M.
Zottmann, A. Niendorf, B. Wolf, „Sensor-Based Cell and Tissue Screening for Personalized
Cancer Chemotherapy“, Medical and Biological Engineering and Computing, vol. 50, pp.
117–126, 2012.
Project title: Verbundprojekt (joint project) „Automatisierte High-Content-Analyseplattform
zur Entwicklung individualisierter Therapiestrategien (AHA)“ (Automated high-content analysis platform for development of individualised therapy strategies (AHA))
Project life span: 1 September 2008 to 31 August 2011
51
Intelligent implant for tumour monitoring [IntelliTUM]
Active implanted systems are becoming more and more important in modern medicine
– not only due to our increasing life expectancy. Intelligent implants are also increasingly
used to record microphysiologic information from selected organs or tissues and for
customising therapy.
During the „IntelliTUM“ project, we developed an implant system for monitoring levels of
dissolved oxygen. The saturation of tissues with dissolved oxygen plays a leading role in
invasive processes in malignant tumours, with the hypoxia (oxygen deficiency) found in
many solid tumours correlating to abnormal metabolic profiles and also sensitivity to radiation therapy. A sensor placed in the direct vicinity of such a tumour may detect increasing hypoxia and provide important information on tumour activity. This may then be used
as the basis for individualised therapy at the appropriate dosage.
Our aim was to utilise the sensors for long-term measurements in vivo: to this end, the
sensors that had already undergone many years of in-vitro testing were further enhanced
during a research project at our faculty that again took several years. This was possible
with the aid of novel technology for recalibrating the sensor in vivo. Further, the sensor
was coated with a specific ionomer membrane which is permeable to oxygen, while preventing proteins from being adsorbed on the sensor and thus minimising biofouling at the
electrodes of the tissue-sensor interface.
Via a bi-directional wireless radio circuit the implant remains in constant contact with
a receiver box transmitting the data to a control station. If signal patterns potentially
hazardous to the patient are detected, the control station can quickly prompt therapeutic
intervention. This approach allows for continuous monitoring of the effects of therapy, thus
eliminating the need for the patient to stay in hospital. In case of a relapse, early interventions are possible at any time.
By using closed-loop implant systems with a topical intracorporeal drug delivery system, it would also be possible to restore a normal quality of life in patients suffering from
diseases that require a systemic treatment involving many side effects. The required actor
interface for the implant was implemented in a follow-up project entitled THEMIC.
Fig.1: Packaging of the implant: the pc
board is folded into the housing. Subsequently, a cover with a window for the
sensor is placed onto the housing.
52
Fig. 2: Vision of the implant system as a
closed-loop application. Depending on
the functional state of the sensor, it is
possible to deliver a chemotherapeutic
agent.
Physician
Publications
S. Becker, Y.Eminaga, D. Hofsöy, J.Clauss, J.Wiest, M.Sattler, M.Brischwein, H.Grothe,
B.Wolf, „Implantable dissolved oxygen sensor system for monitoring disease and healing
processes“, Proceed-ings Deutsches Biosensor Forum 2011, ISBN 978-3-00-034073-4,
p.30, April 3-6, 2011, Bad Heiligenstadt.
S. Becker, Y. Eminaga, D. Hofsöy, K.-U. Hinderer, H. Zhang, A. Sifferlinger,M. Brischwein,
H. Grothe und B. Wolf, „Towards a closed-loop diagnostic and therapeutic implantable
system for tumours“, Proceedings Smart Systems Integration 2011, ISBN 978-3-80073324-8, paper 41, March 22-23, 2011, Dresden.
S. Becker, T. Xu, F. Ilchmann, J. Eisler B. Wolf, „Concept for a gas-cell-driven drug delivery system for therapeutic applications“, Proceedings of the Institution of Mechanical
Engineers, Part H: Journal of Engineering in Medicine, DOI: 10.1177/0954411911423348.
S. Becker, Y. Eminaga, D. Hofsöy, J. Wiest , J. Clauss, M.Sattler, und B.Wolf, „Intelligent
implants for monitoring the hypoxia status of tissue“, BMT 2010; 55 (Suppl 1) pp.4-5, 44.
DGBMT Jahrestagung, October 5-8, 2010, Rostock.
S. Becker, B.Wolf, „Aktive Implantate in der Tumourtherapie“, DZKF Deutsche Zeitschrift
für klinische Forschung, 16. Jahrgang (16th year), 03/04 2012.
J. Clauss, S. Becker, M. Sattler, B. Wolf, „In vivo Diagnostik mit intelligenten Implantaten“,
In: Bern-hard Wolf (Hg.): Bioelektronische Diagnose- und Therapiesysteme. m3: microelectronic meets medicine. 1. Aufl. 2012 (1st edition), Aachen: Shaker Verlag, p. 237–246.
ISBN: 978-3-8440-0831-9.
Project title: „Realisierung eines sensorgestützten intelligenten Implantats zum minimalinvasiven
Tumour-Monitoring mit Telemetrieanbindung – Intellitum“ (Implementation of a sensor-based
intelligent implant for minimally-invasive tumour monitoring with a telemetry link – Intellitum)
Project life span: 1 March 2009 to 30 April 2011
53
Closed-loop microsystem for tumour therapy [THEMIC]
In modern diagnostics and therapy, the role of in-situ measurements and the in-situ
delivery of drugs is becoming more and more important. Physiological parameters, such
as dissolved oxygen in close proximity to a tumour, are important indicators for tumour
growth and therapeutic response. In the preceding „IntelliTuM“ project, an intelligent
implant for measuring dissolved oxygen was developed which can be used for tumour
monitoring.
The THEMIC project investigated the key technologies needed to extend the existing implant system (a purely diagnostic system) to become a closed-loop system. The system
enables a precisely defined dose of an agent used in local chemotherapy to be delivered
in the direct vicinity of the tumour in response to a validated sensor signal. Drug delivery
according to tumour growth and substantially smaller total drug volumes allow for a substantial reduction in side effects for the patient compared to systemic therapy, while leading
to a higher local drug concentration due to localised application. The research work focuses on the actuator technology required for local drug delivery and on new power supply
concepts for meeting the increased energy requirements of such closed-loop systems.
Commercially available systems for microdosing are either too large or unsuitable for implantation. We designed a prototype for a drug delivery system in this project based on a
gas generation cell for producing electrochemical gas within in chamber, causing expansion of a latex membrane and enabling the administration of very small amounts of a drug.
As the functionality of the closed-loop system expands, the power consumption of these
implants will also increase. Wireless power transmission would offer a long product lifetime without having to explant the system in order to replace the battery. As a part of the
THEMIC project, we have developed an inductive wireless energy transmission system
designed to power an intelligent implant system.
The THEMIC and IntelliTUM projects have demonstrated the basic feasibility of an implantable pO2 sensor system for tumour therapy, with the results having been validated
experimentally. The next step will be to test this implant system in eligible in-vivo models.
Oxygen sensor
Fig. 1: Diagram of a prototype system
with foldable electronic unit, sensor
chip and integrated drug delivery
system.
54
Analogous and digital electronic unit, power supply and
radio module
Drug delivery unit
Publications
S. Becker, T. Xu, F. Ilchmann, J. Eisler B. Wolf, „Concept for a gas-cell-driven drug delivery system for therapeutic applications“, Proceedings of the Institution of Mechanical
Engineers, Part H: Journal of Engineering in Medicine, DOI: 10.1177/0954411911423348
S. Becker, Y. Eminaga, D. Hofsöy, K.-U. Hinderer, H. Zhang, A. Sifferlinger,M. Brischwein,
H. Grothe und B. Wolf, „Towards a closed-loop diagnostic and therapeutic implantable
system for tumours“, Proceedings Smart Systems Integration 2011, ISBN 978-3-80073324-8, paper 41, March 22-23, 2011, Dresden.
J. Clauss, S. Becker, M. Sattler, B. Wolf, „In vivo Diagnostik mit intelligenten Implantaten“.
In: Bern-hard Wolf (Hrsg.): Bioelektronische Diagnose- und Therapiesysteme. m3: microelectronic meets me-dicine. 1. Aufl. (ed.) 2012, Aachen: Shaker Verlag, pp. 237–246.
ISBN: 978-3-8440-0831-9
Project title: Verbundprojekt „Biomechatronisches Therapie-Mikrosystem für die Tumortherapie – THEMIC“ (Joint project „Biomechatronic therapy microsystem for tumour
therapy – THEMIC“)
Project life span: 1 April 2010 – 30 June 2011
Fig. 2: Concept of a closed-loop system
55
Therapy modules and systems
“Der Arzt im Gepäck” (A doctor always at hand)
The project „Der Arzt im Gepäck“ was used to develop a gait pattern authentification unit
for use with telemedical support systems.
The aim of this project was to develop an authentification system for assigning individuals
to medical devices based on their unique patterns of movement. To this end, a person‘s
unique kinetic pattern is used for identification. A movement detector strap worn across
the chest is used to detect the degree of two-dimensional acceleration, with the data
obtained permitting the individual gait type to be identified using a pattern detection system. This pattern is assigned to the corresponding individual. The signals are processed
in the chest strap itself, and the data thus acquired are transmitted to a mobile phone. A
mobile phone enables the creation of a self-organised network and facilitates connection
to medical databases and health care providers. This system is particularly useful if it detects the individual kinematic movements while correlating these data with the pulse rates
measured at the same time. Figure 1 depicts the chest strap system, enabling telematic
detection of movements and loads.
Kinetic types may be classified according to various criteria: On the one hand they may
be classified according to a person‘s energy consumption, on the other hand kinematic
movement patterns may be used as classification parameters. The system is thus able
to differentiate between various gaits (slow walking, fast walking, jogging, running), the
number of steps taken as well as the physical load (see Fig. 1, right).
By developing a time series algorithm, we have produced a method suitable to detect
individual gait patterns, as illustrated in Fig. 2.
Fig.1: Left: Prototype for kinetic pattern detection, implemented as a multiparametric chest strap with integrated acceleration measurement system, real-time clock, ECG recording system, and a Bluetooth transmission unit.
Right: Using the kinetic data recorded by the chest strap, various gait patterns may be identified based on the signal patterns measured.
time [s]
56
Pattern 2
Pattern 3
Fig. 2: Histograms of the individual gait
patterns of two different test persons
Subject 2
Subject 1
Pattern 1
Publications
A. Scholz in Jörg Eberspächer, Arnold Picot, Günter Braun: „eHealth: Innovations und
Wachstums-motor für Europa“ chapter 18, pp. 261- 268, Springer 2005.
A. Scholz, V. Lob, J. F. Clauss, J. M. Herrmann, B. Wolf: „Einbindung von Sensorsystemen
in das TPHM-System“, Biomedizinische Technik Vol. 49, pp. 224-225, 9/2004.
This research was funded by the co-operation partner Siemens AG Communications,
München.
Project title: „Der Arzt im Gepäck“ eine Entwicklungsplattform zur selbstorganisierten
drahtlosen Ver-netzung physikalischer und biomedizinischer Sensoren, („A doctor always
at hand“, a platform for the development of self-organised wireless linking of physical and
biomedical sensors)
Project life span: December 2004 to December 2007
57
An intelligent splint for the diagnosis and treatment of teeth grinding
Bruxism is defined as the non-functional grinding, gnashing and chattering of the teeth,
and clenching of the jaw. Today, 5-10% of all adults suffer from bruxism. Bruxism may
occur during the daytime, as well as when sleeping, and is largely a subconscious habit.
In most cases, the habit of teeth grinding is caused by emotional factors, since bruxism
is a way of compensating for feelings of stress, anxiety or depression. Typical symptoms
include wear on the teeth, pain in the muscles and jaw, but also headache and neck pain.
For initial therapy, patients often wear a custom-made plastic splint (occlusal splint) to
protect the teeth.
One of our projects, funded by the „Exist-Seed Förderung“ foundation of the Bundesministerium für Wirtschaft und Technologie, involved the development of a wireless measuring system for bruxism („SensoBite“) which can be integrated into conventional occlusal
splints thanks to its minimal size (see Fig. 1).
The patient‘s chewing activities are measured by means of a piezo-electric sensor system.
A wireless radio transmitter sends the measured data to a receiver the size of a matchbox
which may be placed at the patient‘s bedside or worn on the body. The receiver is able to
receive and store the data over a period of several months. Via a USB interface, the stored
data can be transmitted to the computer of the attending physician. This system allows
the bruxism activity to be monitored both during the daytime and during sleep without
disturbing the patient.
Software for analysing the timing, intensity and frequency of the teeth grinding activity
complements this system. From the recorded measurements, it is possible to identify the
individual causes for bruxism and to derive an appropriate and personalised therapy for
the patient. This system can also prompt immediate tactile (vibration) or acoustic biofeedback via the receiver. In the long run, this biofeedback stimulation will help to condition
the patient and to reduce his/her bruxism activity.
Fig. 1: Occlusal splint with integrated sensor chip
Publications
Fig. 2: Complete system including:
occlusal splint (1); tactile biofeedback
K. Vahle-Hinz, J. Clauss W.-D. Seeher, B. Wolf, A. Rybczynski, M.O. Ahlers,”Development
of a wire-less measuring system for bruxism integrated into occlusal splint”. Journal of
Craniomandibular Function vol. 1, No. 2, pp. 125, 2009.
system (2); front-end computer (3)
K. Vahle-Hinz, J. Clauss W.-D. Seeher, B. Wolf, A. Rybczynski, M.O. Ahlers,”Development
of a wireless measuring system for bruxism integrated into occlusal splint”. World Congress on Medical Physics and Biomedical Engineering 2009, IFMBE Proceedings 25/XI,
pp.108.
K. Vahle-Hinz, J. Clauss, B.Wolf, O.Ahlers, „Vergleich eines drahtlosen Bruxismussensors zur Integration in eine Okklusionsschiene mit EMG-Messungen“, DGFDT 2008 – 41.
Jahrestagung der Deutschen Gesellschaft für Funktionsdiagnostik und Therapie – Bad
Homburg, 28 Nov. - 29 Dec. 2008.
This research was funded by the Bundesministerium für Bildung und Forschung (ExistSeed).
Project title: „System zur Diagnose und Therapie von Bruxismus“ (System for the diagnosis and therapy of bruxism)
Project life span: 1 May 2005 to 30 April 2006.
59
Tone and tonus
The „Tone and Tonus“ project examined the acoustic intervention options relevant to the
treatment of hypertension and other stress-related disorders. Our research team investigated the options for modulating the autonomic nervous system with non-pharmacological
therapies and the related control mechanisms in human physiological processes.
We use modern information and communications technologies as an interdisciplinary and
practical approach. Telemedical assistance systems and consumer electronic devices
must be closely interlinked with medical applications. We used our „Virtual Lab“ (cf. article
13) to specifically investigate the antihypertensive effect of certain iterative sound patterns
as a possible intervention in patients suffering from arterial hypertension. The antihypertensive effect of particular pieces of music and iterative sound patterns is a frequently
described phenomenon [1, 2].
It has been demonstrated that when collecting physiological data from humans, quality
very much depends on parameters like location and time [3,4]. The so-called „white coat
effect“ is just one example of the influence psycho-physical reactions may have on physiological measurement signals. The use of a virtual lab supported by telemedicine results
in increased patient compliance and better correlation of the patient‘s own blood pressure
measurements with his/her current state of health compared with measurements taken
in the clinical setting [3]. Furthermore, the virtual lab enables us to find solutions to the
practical medical problems we are facing today.
The system is not limited to measuring blood pressure, however; it can also be used to
generate complex intervention-correlated data patterns by integrating further sensors.
Since our system can collect and transport any type of physiological data, it it can be
used in the development of various physical or musical biofeedback therapies. In order to
allow for individualised therapy, an evaluation of the circadian or gender-specific efficacy
and compliance structures is also necessary. The virtual lab environment is therefore an
ideal development and test platform for personalised treatments as well as for other music
therapy concepts. Acoustic interventions have already been integrated into our cognitive
medical system COMES®.
Further scientific questions in this context are addressed by integrating the fields of psycho-education, surrogate therapies, activity focused prevention and rehabilitation, as well
as Ambient Assisted Living (AAL).
[1] R. Spintge, R. Droh, „MusicMedicine“, Barcelona Publishers 1992.
[2] H.-P. Hesse, „Musik und Emotion“, Springer, Vienna 2003.
[3] F. McAlister, ”Measurement of blood pressure”, BMJ: 322, 2001.
[4] M. Middeke, „Arterielle Hypertonie“, Stuttgart 2005.
60
Fig.1: Acoustic interventions as a component of our cognitive medical system
COMES© (Cognitives Medizinisches
System)
Publications
P. Friedrich, „Etablierung einer telemedizinisch gestützten bioakustischen HypertonieTherapie mittels Virtual Lab“, Dissertation at the Heinz Nixdorf-Lehrstuhl für Medizinische
Elektronik, Technische Universität München, 2010.
Research has been ongoing in this field since 2005. Until 2011 this research was funded
by the Heinz Nixdorf Stiftung and the Siemens AG.
Meanwhile, this project has been continued and expanded by the KoKeTT institute at the
Hochschule Kempten in cooperation with the Heinz Nixdorf-Lehrstuhl für Medizinische
Elektronik of Technische Universität München.
61
Enrichment and detection of molecules secreted by tumour cells using magnetic
nanoparticles and LC-MALDI-TOF mass spectroscopy
Cells communicate through a network of different substances, including cytokines, interleukins and hormones. The synthesis and partly also the secretion of such substances reflect the functional state of the cells. In the case of tumour cells, the progression to states
of increasing malignancy is accompanied by changes in gene expression.
Peptides or proteins that are secreted by tumour cells at different stages during the
pro-cess of neoplastic degeneration could be possible candidates in the search for new
biomarkers to further improve tumour diagnostics. However, cancerous cells secrete only
very low amounts of peptides or proteins (concentrations in the range of 10-12 to 10-9
mol/L). Therefore, a large number of cells (108 to 109) are needed to obtain sufficient
material for successful mass spectrometric analysis. Cancer cells are usually cultivated in
a medium containing foetal calf serum, though this entails considerable background noise
in the spectra.
In this study, MCF-7 and MDA-MB231 cells (model lines for various stages of progression of human breast cancer) were successfully cultivated and propagated under serumfree culture conditions. We also successfully isolated the secreted substances from the
serum-free supernatant, and concentrating them with magnetic reversed-phase particles.
Microparticles and nanoparticles offer the advantage of having an extremely large surface
which is able to efficiently and reversibly bind proteins and peptides from complex solutions. It is particularly important to adapt the chemical surface of these particles precisely
to the desired process. After binding, the particles are washed and the substances eluted.
After separating the substances by liquid chromatography (LC), it is possible to generate
reproducible signal patterns by using a method called „matrix-enabled laser desorption“,
coupled with a „time-of-flight“ analysis of the substances.
The signal patterns thus obtained from one cell line differ substantially from those of the
other cell line. It was possible to detect small volumes of the substance even down to 100
femtomole/mL.
A primary goal of this project was more efficient screening for „tumour biomarkers“, but
we assume that the methods employed may also be used for follow-up tests in cancer
patients. They could help with early detection of recurring tumour activity after therapy.
We are currently doing intensive research in order to solve the issue as regards the serum
background.
In principle, the sampling process can be aligned with the IMOLA and AHA platforms,
making it possible to also detect the relevant peptide profiles in addition to unaddressable
profiles.
62
Fig. 1: Profiles of peptides secreted by MCF-7 and MDA-MB231 cells, represented in a 3D diagram. The vertical dimension stands for
the relative substance volumes, the horizontal one for the retention time in liquid chroma-tography. Cell-culture supernatants (DMEM
+ 5% serum surrogate) collected 0 h and 48 h after changing the medium were purified and analysed. (A) Cell-free control after 0 h, (B)
MC F-7 cells after 0 h, (C) MD A-MB231 cells after 0 h, (D) cell-free control after 48 h, (E) MC F-7 cells after 48 h, (F) MD A-MB231 cells
after 48 h. The diagram clearly depicts the different cell-specific secretion profiles that provide data on functional behaviour.
Publications
J. Peter, A. Otto, B. Wolf, „Enrichment and Detection of Molecules Secreted by Tumour
Cells Using Magnetic Reversed-Phase Particles and LC-MALDI-TOF-MS“, Journal of Biomolecular Techniques, Volume 18, Issue 5, December 2007, pp. 287-297.
The method introduced in this article is currently one of the most sensitive methods for the
simulta-neous detection and characterisation of peptides and proteins. For his research
in this field, Dr. Jochen Peter received the Outstanding Scientist/Technologist award from
the international organisa-tion ABRF in the USA in March 2007, and the Young Investigator Award in Proteomic Sciences from the HUPO in Korea in October of the same year.
63
Cell transfection, targeting and positioning of agents marked with nanoparticles
using static and dynamic magnetic fields
This project entailed the investigation of a method for directing magnetic nanoparticles
coupled with an appropriate drug to any site of the human body by applying an external
magnetic field (Magnetic Drug Targeting, MDT). This is done after endovascular application of the particles. This promising new method could be useful in cancer therapy, its aim
being to direct high concentrations of a therapeutic substance solely to the area of the
tumour. In practice, the medicine could be administered into an artery or vein and could
then be controlled by an external magnetic field and directed towards the desired region.
It is also conceivable that such localised cancer treatment could be applied in the form of
an aerosol for pulmonary diseases.
In the past, several carrier systems were developed for specifically transporting therapeutic agents. The MDT method allows the drug chosen for the patient to accumulate in
a particular part of his/her body by means of magnetic nanoparticles and magnetic fields.
The molecules of a pharmaceutical substance are chemically coupled to active components (e.g. magnetite) and thus transferred to a pharmaceutically stable micro-carrier
system.
For clinical applicability, it must be ensured that the nanoparticles are biocompatible,
e.g. by coating the magnetic particles with biopolymers such as starch. Recent studies
have revealed that with particles treated in this way, undesirable side effects can almost
be eliminated entirely. This coating is also necessary for preventing the particles from
aggluti-nating due to Van der Waals forces. Further, in the case of intravascular application
of nanoparticles it is extremely important to take the local flow characteristics within the
bloodstream into account. Among others, these are influenced by the size and the material of the particles. These characteristics are crucial to pharmacokinetics and the attainable
enrichment factor.
We developed a physical model in this project that simulates various types of flow characteristics in order to be able to predict the behaviour of the individual particles.
Liquid culture
medium
and nanobeads
pump
magnetic coil
cell culture
Fig. 1: This model illustrates a blood
vessel in which particles get immobilized against the blood flow through
magnetic fields.
64
cell chip
magnetic yoke
Fig. 2: Illustration of the Magnetic Drug
Targeting system (right) compared
to a passive method (left). When
the magnetic particle/active agent
complexes reach the perfusional area of
the tumour, only a few will flow into the
tumour if no magnetic field is applied,
whereas a large number will migrate if a
magnetic field is present. Thanks to the
magnetic field, the particles are drawn
into the tumour and will also remain there. [Image modified according to www.
Publications
gcarlson.com].
C. Dahmani, T.Weyh, H.-G. Herzog, „A simplified Approach for Nanoscale Magnetic Moment Meas-urement and a Study of the Impact of Nanoparticle Interaction on their total
Magnetic Moment“, Pro-ceedings of the conference Seeing at the Nanoscale VII - Exploring the future of Nanotechnology Using SPM and related Techniques, Santa Barbara,
California, 28-31 July 2009; California NanoSys-tems Institute; 2009.
C. Dahmani, S. Götz, T. Weyh, R. Renner, M. Rosenecker, C. Rudolph, „Respiration triggered Mag-netic Drug Targeting in the Lungs“, Proceedings of the 31st Annual International
Conference of the IEEE Engineering in Medicine and Biology Society, Minneapolis, 2-6
September 2009; IEEE; 2009.
C. Dahmani, F. Helling, T. Weyh, C. Plank, „An Innovative Rotational Magnetic System to
enhance Cell Transfection with Magnetic Nanoparticles“, Proceedings of the World Congress for Medical Physics and Biomedical Engineering 2009, München, 8-11 September
2009; VDE; 2009.
Project title: „Verbundvorhaben Nanomagnetomedizin: Teilvorhaben: Zell-Transfektion,
Targeting und Positionierung von Nanopartikel-markierten Wirkstoffen durch statische
und dynamische Magnetfelder“ (Joint project Nano-magneto-medicine: Subproject: cell
transfection, targeting and positioning of agents marked with nanoparticles using static
and dynamic magnetic fields)
Project life span: 1 January 2007 to 31 December 2009
65
Investigation of the inhibition of pathogen adhesion to intestinal cells caused by
oligogalacturonic acids (OGAs) using chip-based in vitro test systems
The human gastrointestinal tract is a biotope-like environment in which intestinal epithelia
and non-pathogenic (i.e. symbiotic and commensal) bacteria co-exist. This sensitive equilibrium may be perturbed by the appearance of pathogenic strains such as Escherichia
coli O157:H7 (EHEC), leading to an infection of the gastrointestinal tract. The adhesion of
pathogenic bacteria to the cells of the intestinal epithelium is assumed to be a key step
in this infection process, which will finally out-compete the physiological intestinal flora.
Figure 2 is a microscopic image of a Caco-2 cell culture used as an in-vitro model for
the intestinal epithelium. The cell culture has been colonised by E. coli bacteria ,some of
which are already firmly adhered to the cells.
In collaboration with the Deutsches Institut für Lebensmitteltechnik e.V. in Quakenbrück
and the Bundesinstitut für Risikobewertung in Berlin, we investigated the detectability of
the adhesion of pathogenic bacteria to intestinal epithelial cells, and studied options for
preventing or at least reducing the effects of such adhesion through the use of food additives. The additive analysed in this project was a hydrolytic breakdown product of pectin
(a component of plant cell membranes), available as a compound of so-called oligogalacturonic acids (OGAs). Quite large amounts of these pectin fractions and OGAs are found
in carrot juice, for example, which is thought to have a preventive or even a therapeutic
effect in cases of diarrhoea. In measurements with a sensor-enabled in-vitro test system,
we have in fact found that certain OGAs exert a very negative effect on the metabolic
activity of E.coli bacteria and may thus be used for therapeutic purposes.
Fig. 1: Unsaturated OGA molecule.
During the hydrolysis of pectin, trimers
or tetramers usually develop (n=2-3).
COOH
O
O
OH
OH
66
COOH
O
O
OH
n
Fig. 2: Left: microscopic image of Caco-2 cells in co-culture with E.coli H10407 cells (1 x 108/mL, 1 hour after co-culture) - image
reproduced with the kind permission of: Deutsches Institut für Lebensmitteltechnik e.V., Abt. Mikrobiologie. Right: extracellular acidification rates of co-cultures of Caco-2 cells and E.coli C.25 (added at 2 h 15 min). While E.coli cells preincubated with OGAs do not lead
to increased acidification, untreated bacteria rapidly colonise the Caco-2 cell culture. The data on extracellular acidification suggest
that the E.coli cells prein-cubated with the OGAs are affected with respect to their metabolic activity, and presumably also with respect
to their adhesion to the Caco-2 cells. This result suggests that OGAs have an antibacterial effect, but it still remains to be seen whether
they have a toxic effect on Caco-2 cells.
Publications
D. Grundl, T. Flurschütz, J. Wiest, B. Becker, M. Brischwein, B. Wolf, „Mathematische Verarbeitungs- und Interpretationsmethoden von metabolischen Signalen lebender Zellen auf
biohybriden Sen-sorchips Biosensor“, 6. Deutsches BioSensor Symposium, 29 March - 1
April 2009, Freiburg, p. 60, 2009.
B. Becker, D. Grundl, M. Schmidhuber, F. Ilchmann, M. Brischwein, B. Wolf, „Automatisches Lab-on-a-Chip Testsystem für cell-based assays“, 6. Deutsches BioSensor Symposium, 29 March - 1 April 2009, Freiburg, p. 147, 2009.
K. Jeongyun, M. Hegde , A. Jayaraman, „Co-culture of epithelial cells and bacteria for
investigating host–pathogen interactions“, Lab on a chip 10, pp. 43-50, 2010.
Project title: „Verbundprojekt: Gewinnung und Charakterisierung von Oligogalacturonsäuren sowie Untersuchungen zur Inhibierung der Anheftung pathogener Keime und Cytotoxine an Intestinalzellen mittels in vitro-Testsystemen“ (Joint project: Sampling and characterising oligogalacturonic acids and investigating the inhibition of pathogenic germs and
cytotoxins to intestinal cells by means of in-vitro test systems)
Project life span: 1 January 2007 to 31 May 2010
67
Isolation of human pancreatic islet cells and quality control: quality control and toxicological testing of immunodepressants with chip-based test systems
Pancreatic islet cells are transplanted in patients suffering from a serious form of type
I diabetes. Despite considerable success in restoring insulin production, in most cases
patients experience a relapse after a short period of time. This occurs on the one hand
because the cells die after transplantation, whilst on the other hand immunodepressants
have been found to exert unexpected toxicity on the islet cells.
For improving the success rates in the transplantation of pancreatic islets, we require a
quality platform allowing for testing the functionality of the donor islets and their sensitivity
to immunodepressants prior to transplantation. A viable approach is measuring the vitality
of isolated islet cells on a bioelectronic sensor chip in real time.
The goal of this project, therefore, was to develop a quality-control platform suitable for
testing the vitality of the isolated islets prior to transplantation using various methods,
and at the same time enabling immunosupressant drugs to be tested. We had intended to
equip this platform with bioelectronic sensor chips on which the islets may be cultivated in
order to measure their metabolic activity in real time.
The primary functionality testing of isolated islets and islet cells in culture was first per-formed by means of antibody detection of glucose-stimulated insulin secretion. At the same
time, islets were cultivated on sensor chips in order to continually monitor the metabolic activity, by measuring the acidification rate and oxygen consumption during glucose
stimulation. The test system was then used to analyse the effect of immunosuppressants.
The sensor chips also permit the vitality of various liver cells (the islets are injected into the
recipient‘s liver) to be measured. To provide conditions similar to the physiological situation,
the islets were cultivated with matrix proteins and inflammatory substances which are produced by immunologically competent cells (interleukins). The laser microdissection method
was employed for differential characterisation since it allows defined areas to be excised
from the islets and their function to be analysed using molecular biology techniques.
Fig. 1: Mouse islet cell samples marked
with a fluorescent dye (green: living
cells, red: dead cells). Fig. 2: Singular
measuring device for a bioelectronic
sensor chip (IMOLA)
68
Fig. 4: The test was performed on 6
parallel chips in an IMOLA incubators.
All in all, we found that the cultivation of
isolated islets on bioelectronic sensor
chips allows for multiparametric analysis
of cell vitality and also offers a good basis
for further applica-tions in medicine.
Fig. 3: Measuring the metabolic activity of islet cells in culture
(INS1E) prior to and after stimulation with a high glucose concentration leading to insulin secretion.
91221 INS1-IM360-600s
69
Publications
F. Yilei, „Optimierung der Kultivierungsbedingungen für die INS-1E Zelllinie im Hinblick auf
die Insu-linsekretion“, Semesterarbeit (assignment), submitted at the Technische Universität München, October 2009.
B. Bergmann, „Funktionale Charakterisierung von INS-1E-Zellen unter verschiedenen Bedingungen zur Stimulation der Insulinsekretion“, Diplomarbeit (dissertation submitted for a
diploma) at the Hoch-schule für Angewandte Wissenschaften, Munich, March 2010.
R. Kleinhans, J. Wiest, A.M. Otto,, „Effects of cytokines on growth and energy metabolism
of insulin secreting cells“, European Journal of Cell Biology 88S1, Suppl.59. p76, Jahrestagung der Deutschen Gesellschaft für Zellbiologie, Universität Konstanz (Constance), 24-27
March 2009.
B. Bergmann, V. Auer, Y. Fu, J. Wiest, A. M. Otto, „Metabolism of beta-cells stimulated to
secrete insulin: real-time monitoring using sensor chips“, Jahrestagung der Deutschen
Gesellschaft für Zell-biologie, Universität Regensburg,10–18 March 2010.
B. Bergmann, V. Auer, E. Janas, V. Ninichuk, J. Wiest, A. M. Otto, „Monitoring Metabolism
of Pancreatic Beta-Cells in Real-time by Using Sensor Chip Technology“, Heinz-NixdorfSymposium, Munich, 12-13 October 2010.
A.M. Otto, „Cell Cultivation and Sensor-based Assays for Dynamic Measurements of Cell
Vitality“, BetaSys - Systems Biology of Regulated Exocytosis in Pancreatic Beta-Cells Eds:
Booß-Bavnbek,B.; Klösgen,B.; Larsen,J.; Pocoit,F.; Renström,E.. Springer Series Systems
Biology 2 Ch. 10, p.221-240, 2011.
Project title: „Humane pankreatische Inselisolation und Qualitätskontrolle“ (Isolation of
human pancreatic islet cells and quality control)
Project life span: 15 August 2007 to 31 December 2010
70
71
Development and evaluation of a monitoring and treatment system for sleep-related
breathing disorders
Studies have shown that more than 20% of the adult population snore regularly during sleep
and that 2% - 4% suffer from obstructive sleep apnoea (OSA), leading to obstruction of the respiratory tract and causing patients to repeatedly wake up. OSA mostly leads to severe daytime
sleepiness and entails an increased risk of cardiovascular diseases. It is therefore an alarming
fact that over 70% of sufferers are yet to be diagnosed, a procedure that normally takes place
at a sleep laboratory. As treatment, patients usually need to wear a continuous positive airway
pressure mask (CPAP mask). However, almost half of snorers and OSA patients could benefit
from an efficient therapeutic approach which prevents them from lying on their backs during
sleep, since these patients suffer from what is referred to as positional sleep apnoea with snoring and OSA, which is mainly caused by sleeping on one‘s back.
Fig. 1: Detection of the signals of snoring and respiratory movement by the
acceleration sensor
72
Fig. 2: Complete system: the different
parameters measured on-line are used
to control therapy
For these reasons, an innovative monitoring and treatment system for sleep-related breathing disorders (SRBD) has been developed and evaluated. The innovative feature of this
system allows parameters such as snoring, heart rate, respiratory movement and sleeping
position to be measured by means of one single acceleration sensor in a headband or
dental splint (see Fig. 1). We were able to demonstrate in a clinical study that it is possible
to automatically detect snoring and provide an indication of the severity of SRBD.
Hence the miniature wireless measuring system may be used for making a diagnosis, but
also for long-term monitoring: it enables routine monitoring of the patient for disease progression and therapeutic efficiency.
Follow-ups delivering conclusive results have so far necessitated elaborate tests in a
sleep laboratory.
73
The automatic detection of snoring and OSA combined with recording the patient‘s
sleeping position make it possible to identify those patients suffering from a positional disorder as well as to monitor the efficiency of positional therapy. By using vibration signals
for biofeedback, implemented as a vibration motor in the headband, we have been able
to demonstrate the success of this intelligent approach to positional therapy. Compared
to the inconvenience of the breathing mask, our system is a comfortable alternative for a
large number of patients suffering from positional sleep apnoea.
Publications
D. A. Hofsøy, J. Clauss, B. Wolf, „An intelligent implant system for monitoring and biofeedback therapy of snoring“, World Congress on Medical Physics and Biomedical Engineering, September 7–12, 2009, Munich, Germany, ISBN 978-3-642-03472-5, pp. 196-199,
IFMBE Proceedings, Volume 25/VIII, Olaf Dössel and Wolfgang C. Schlegel, Springer
Heidelberg, 2009.
D.A. Hofsøy, J. Clauss, B. Wolf, „Monitoring and therapy of sleep-related breathing disorders“, 6th International Workshop on Wearable Micro and Nano Technologies for Personalized Health (pHealth), June 24– 26, 2009 in Oslo, Norway, ISBN 978-1-4244-5252-1, DOI
10.1109/PHEALTH.2009.5754827, pp. 41-44, IEEExplore, 2009.
This research was funded ba the Bund der Freunde der TU München e.V. and the Heinz
Nixdorf Stiftung.
Project title: „Intelligentes Implantatsystem zur Diagnose und Therapie von Schnarchen
und Schlafapnoe“ (Intelligent implant system for the diagnosis and treatment of snoring
and sleep apnoea)
Project life span: 5 August 2008 to 4 August 2009
74
75
Analysing the therapeutic relevance of the transmembrane potential of tumour cells
[EvoPot]
Cells are electrodynamic systems and may be described by defined input and output
variables. Electric activity at the cellular level is caused primarily by moving ions, leading
to generator potentials at selective membranes permeable to ions. Fig. 1 is an electron
microscope image of a colonic epithelial cell. It is clear from this picture that the structural
cell components mainly consist of membranes, and that the nanostructured compartmentation of the cell is elicited by electroactive membranes.
Binggeli and Weinstein (see Fig. 2) have shown that with almost all the cell types ex-amined, the transition from stationary to proliferative behaviour is characterised by a change
in the transmembrane potential. The trigger threshold was found to be approx. 37 mV, and
depending on whether the potential is increased or decreased, the tendency of the cells to
divide will also change [1].
Surprisingly, this value is true for both tumour and non-tumour cells, which suggested that
an evolutive concept must be the underlying principle.
The EvoPot project demonstrated that the growth rate of cells may be influenced by
applying electric and magnetic fields, and that growth may be reduced significantly under
certain conditions.
In therapies involving electric fields, the field strengths are within a technically feasible
range most unlikely to pose any regulatory problems when it comes to developing a new
cancer therapy. Surprisingly, however, we have found that therapy using magnetic fields
requires very high magnetic field strengths. Nevertheless, we also found that the influence
of magnetic fields reduces growth by approx. 30-40%.
From the data obtained during the EvoPot project, it can be seen that a permanent field
exposure over a period of at least one hour is required for a therapeutic effect. In this project, the principles of using a field-enabled influence on the membrane potential for cancer
therapy were investigated for the first time ever. During our experiments, we found that
not all information found in literature was correct, as was the case with some assumptions
as regards an available apparatus system that may be appropriate here. However, thanks
to the presently available technical options some of which were provided by other project
groups, we are able to perform the experiments that are still necessary in a highly parallel
and a statistically well-established manner. Further, the data thus acquired were used for
designing therapeutic implants
[1] R. Binggeli, R.C. Weinstein, Membrane potentials and sodium channels (1986): Hypotheses for Growth regulation and cancer formation based on changes in sodium channels
and gap junctions, J.theor.Biol.123, 377-401
76
Fig. 1: Electron microscope image of a colonic epithelial cell
Fig. 2: The transmembrane potential of normal animal cells (right) and of transformed
tumour cells (left). It can be seen that proliferating cells have a transmembrane potential exceeding a threshold value of approx. -37mV. Cells able to assume a transitory mitotic state thereby decrease the value of their transmembrane potential. The red blood
cell, an anuclear cell with special functions, is an exception to this rule. According to
data provided by Binggeli and Weinstein 1986.
Fig. 3: Influence of the exposure of MDA-MB231 cells to an electric field on their growth
Fig. 4: Influence of the exposure of L929 cells to the magnetic field on their growth
after 71h and 95 h in culture on glass chips (electric field strength: E=250 V/m).
after 71h and 95 h in culture on glass chips (magnetic field strength: B=35 mT).
5.0
Control
After 21 hrs of exposure
2.5
n=6
2.0
1.5
n=6
n=6
1.0
n=6
Cell density in culture [cells/cm2]*105
Cell density in culture [cells/cm2]*105
3.0
4.5
Control
After 17 hrs of exposure
4.0
n=6
3.5
3.0
2.5
2.0
1.5
n=6
n=6
n=6
1.0
0.5
0.5
71
time[t]
95
71
time[t]
95
77
Publications
B. Wolf, L. Hafner, M. Brischwein, H. Grothe,M. Remm, A. Michelfelder: EvoPot:Konzepte
für eine bioelektronische Tumortherapie. In: Bernhard Wolf (Hg.): Bioelektronische Diagnose- und Therapie-systeme. m3: microelectronic meets medicine, 1. Aufl. 2012, Aachen:
Shaker Verlag, pp. 139–146. ISBN: 978-3-8440-0831-9
L. Hafner, B. Wolf: Feldinduzierte metabolische Veränderungen an Tumorzellen. In: Bernhard Wolf (Hg.): Bioelektronische Diagnose- und Therapiesysteme. m3: microelectronic
meets medicine, 1. Aufl. 2012, Aachen: Shaker Verlag, pp. 139–146. ISBN: 978-3-84400831-9
Project title: „EvoPot - Analyse der therapeutischen Relevanz des Transmembran-Potenzials von Tumourzellen mittels multiparametrischer bioelektronischer Chipsysteme“ (EvoPot
- Analysing the therapeutic relevance of the transmembrane potential of tumour cells by
multiparametric bioelectronic chip systems)
78
79
Multiparametric system for automated high-throughput analysis of nerve cells
[neuroscreening]
In recent years, the investigation of living cell cultures using miniaturised sensor systems has become more and more important in medicine and in pharmaceutical research.
Nerve cells are used as biological sensors and signal conductors in a large number of our
research endeavours. This includes the evaluation of the effectiveness of new drugs and
the investigation of their neurological side effects, as well as environmental analytics for
testing the neurotoxicity of pollutants.
Based on the know-how gained during the preceding „EvoPot“ project, one of our teams
has focused on detecting various metabolic and morphological parameters in coherent
neuronal networks. Since nerve cells, the so-called neurons, communicate via electric potential variations, it is of great importance to find a way of detecting these signals in order
to investigate complex interneuronal relationships, as well to develop drugs for influencing these functions, e.g. drugs for the treatment of neurodegenerative diseases such as
Alzheimer‘s or Parkinson‘s disease.
Aiming to investigate the behaviour of neuronal cell layers in greater detail, and to find a
solution for measuring their interactions, we make use of extracellular measuring techniques. These do not harm the neurons and therefore allow for long-term measurements.
The multi-electrode arrays (MEAs) we had developed and miniaturised particularly for this
purpose are able to detect the electric cell signals with an array of tiny conductive electrode structures and to transmit them to external monitoring amplifiers which are part of the
so-called NeuroPlate.
Fig. 1: Layout of the chip structures
used. The insulated conductor patterns
are shown in green, de-insulated ones
in blue
80
Fig. 2: Detailed view of the NeuroPlate.
For statistical validation of the data thus acquired, we also developed a specific system
for collimating the individual measurements. The basis of the NeuroPlate is formed by a
carrier in the format of a multi-well plate with 24 individually equippable wells for the MEA
glass sensor chips (neuro-chips) that can be microscopied during measurement. Every
neuro-chip already has a vessel fixed to it, holding the culture medium required for the
long-term measurements.
The central feature of the NeuroPlate is its integrated signal processing unit. The electrical
signals derived from the 32 microelectrodes of every single chip undergo analog pre-amplification and filtering, a process performed separately in each chip. The channels may be
controlled separately and amplified with variable amplification factors, and A/D conver-sion of the signals may be performed within the NeuroPlate. An optional data compression
function helps to transmit the data volumes to a computer.
81
Fig 4: visualisation of the derived action
potentials in a cell culture at the measurement station; right:
Fig. 3: Display depicting the activities in
a cell culture.
82
Publications
Ilchmann, F., Grundl, D., Lob, V., Becker, B., Wolf, B., „Zell-Chipsysteme - Mikrosensorarrays für die biologische Grundlagenforschung und Diagnostik“, GIT Laborfachzeitschrift,
52. Jahrgang (52nd year), 3 March 2008, pp. 260-285.
Ilchmann, F.; Weiß, R.; Trappendreher, D.; Becker, B.; Schmidhuber, M.; Wolf, B.: Multiparametrisches NeuroScreening-System für automatisierte Hochdurchsatz-Analyse. In:
Bernhard Wolf (Hg.): Bioelektronische Diagnose- und Therapiesysteme. m3: microelectronic meets medicine, 1. Aufl. 2012, Aachen: Shaker Verlag, pp. 139–146. ISBN: 978-38440-0831-9
J. F. Meyer, F. Kamp, T. Bartels, T. N. Kinney, F. Ilchmann, K. Beyer, B. Wolf, „MEA supported corti-cal cultures as a novel tool in Alzheimer’s research“, Proceedings 6th International Meeting on Sub-strate-Integrated Micro Electrode Arrays, Reutlingen, 2008
F. Ilchmann, J. F. Meyer, J. Ressler, H. Grothe, B. Wolf, „Multiparametric NeuroLab recording chamber with MEA and integrated metabolic sensors“, Proceedings 6th International
Meeting on Substrate-Integrated Micro Electrode Arrays, Reutlingen, 2008
Ilchmann, F.; Trappendreher, D.; Becker, B.; Heise, G.; Wolf, B.: Laserbasierte Herstellungsverfahren individualisierbarer Biosensorchips. In: Bernhard Wolf (Hg.): Bioelektronische Diagnose- und Thera-piesysteme. m3: microelectronic meets medicine. 1. Aufl.
2012, Aachen: Shaker Verlag, pp. 131–138. ISBN: 978-3-8440-0831-9
Becker, B., Etzbach S., Schmidhuber M., Grundl D., Ilchmann F., Grothe H., Wolf, B. Realtime Screening System using living cells for chemosensitivity testing, The IEEE Region
8 Eurocon 2009 Conference, 18 -23 May 2009, Saint-Petersburg, Russia, ISBN 978-14244-3860-0, pp. 87-93, INSPEC Accession Number: 10791108, Digital Object Identifier:
10.1109/EURCON.2009.5167609
Project title: „EvoPot - Analyse der therapeutischen Relevanz des Transmembran-Potenzials von Tumourzellen mittels multiparametrischer bioelektronischer Chipsysteme“ (EvoPot
- Analysing the therapeutic relevance of the transmembrane potential of tumour cells by
multiparametric bioelectronic chip systems)
83
Therapeutic magnetic stimulation
In neuro-rehabilitation, magnetic stimulation has been postulated as a promising treatment option. Our „Therapeutic magnetic stimulation“ project involved the development
and de-sign of a new magnetic stimulation system for therapeutic purposes for testing in
humans.
In medicine, the electric and magnetic stimulation of nerves and muscles is an established
method for diagnostics, therapy and rehabilitation. This project aimed at significantly enhancing the efficiency of the relatively new „Therapeutic magnet stimulation“ method and
opening the door to new fields of application in medicine.
The electrical stimulation of large muscular surfaces is associated with substantial pain
in the patient/subject, and only allows for the stimulation of muscles lying under the skin
sur-face. In contrast, magnetic stimulation permits muscle contractions to be triggered
without activating the pain pathways, and penetrates deeper into the muscular tissue. Due
to the beneficial magnetomotive force acting on the muscle, it is possible to make use of
substantially stronger muscle forces while causing less fatigue.
In our project, we developed, designed and tested a new magnetic prototype system
which for the first time ever uses a high-frequency polyphase „BURST“ as a stimulation
pulse. With a view to clinical use, the new stimulation system was tested in humans for its
therapeutic and rehabilitative effects and its energy efficiency.
Test series were performed to determine the optimum number of cycles in subjects with
total paraplegia compared to healthy subjects. We found that the effectiveness of peripheral repetitive magnetic stimulation may be increased by using pulse trains (BURSTs) with
3-4 cycles. We further assume that peripheral repetitive magnetic stimulation may have a
strong alleviating effect on spasticity.
Fig.1: Real-life measurement set-up
(photo: Dr. Szecsi, Klinikum Großhadern)
Fig. 2: Principle of the test installation
FES
1
2
Laptop
FMS
for rehabilitative magnetic stimulation
2
C
M
84
Motor
Publications
Therapeutische Magnetstimulation, BFS-Forschungsberichte 2010, p. 38.
J. Szecsi, N. Gattinger, B. Gleich, H. Grothe, S. Götz, H.-G. Herzog, M. Jaschke, K. Wendicke, H. Zantow, and A. Straube, „Perspektiven der peripheren funktionellen Magnetstimulation in der Rehabi-litation zentraler Lähmungen“, Biomedizinische Technik, 2010.
M. M. Beck, N. Gattinger, S. Götz, D. H. Schmid, J. Szecsi, H. Zantow, K. Wendicke, A.
Straube, H.-G. Herzog, and B. Gleich, „2-Channel Magnetic Stimulator For Peripheral Muscle Stimulation Of Paretic Patients“ In: Technically Assisted Rehabilitation, 2011.
A. Pechamann, I. Delvendahl, T. O. Bergmann, C. Ritter, G. Hartwigsen, B. Gleich, N. Gattinger, V. Mall, and H. R. Siebner, „The number of full-sine cycles per pulse influences the
efficacy of multicycle transcranial magnetic stimulation“, Brain Stimulation, 2011.
J. Szecsi, B. Gleich, N. Gattinger, and A. Straube, „Functional magnetic stimulation as a
supposedly 'painless' option for movement induction in plegics“, Fortschr Neurol Psychiatr, 2011.
N. Gattinger, G. Mößnang, B. Gleich, „flexTMS - A novel repetitive transcranial magnetic
stimulation device with freely programmable stimulus currents“, IEEE Trans Biomed Eng,
2012.
This research was funded by the Bayerischen Forschungsstiftung.
Project title: „Therapeutische Magnetstimulation“ (Therapeutic magnetic stimulation)
Project life span: 2008 – 2010
85
The “Lufttacho”: Sensors get wings
The measurement of air flows may be useful in medicine and also in many other fields
of research. While the principle of hot-wire anemometry for measuring the mass flow of
gas has long been known, the fabrication of such a sensor has remained too elaborate
and cost-intensive. In cooperation with the company sendsor GmbH, we have worked on
finding a new and cost-effective production process for this type of sensor. Compared to
conventional mass flow sensors, these sensors offer the advantage of a broader measurement range and higher measurement accuracy, especially in the case of lower flow.
Plating any type of metal structure intended for electronic circuits on injection-moulded
carrier substances offers a very efficient option for the production of microsensor devices.
Figure 1 gives an example of a simple structure made from a nickel-galvanised polymer,
the surface of which reveals meander-like structures formed by means of a CO2 laser.
Thanks to the geometrical design and the selection of various metals, it is possible to
fabricate structures with the desired resistance value and temperature dependence or
resistance in a fast and cost-effective manner.
Thanks to the simplified fabrication process, it is also possible to rapidly adapt the specific characteristics of the sensors to the requirements of every application.
The spirometer, or „Lufttacho“, which was especially developed for children, entails the
direct use of the hot-wire anemometry principle mentioned above. The innovative hot-wire
anemometry technology allows even for small volume flows to be detected.
Owing to the simplicity of this technology, the pre-calibrated sensor unit may be replaced
in a similar way as the mouthpieces of comparable spirometers. Hence this system does
not needs to be calibrated by the user, a process which often is a source of error in other
measurement systems. The tube may be disinfected and disposed of after a predetermined number of applications, which helps to minimise cross-infections.
The „Lufttacho“ was developed by sendsor GmbH and is the first electronic spirometer
specifically designed for children. The measurement range was adapted to the small lungs
of children and allows for the precise and reliable measurement even of values under 300
L/min. The „Lufttacho“ is the first ever system to enable the patient and physician to use
one and the same device for measurement. Besides its diagnostic feature, the device
also comprises a game that was specifically developed for children and enables them
to use the device for respiratory training. The colour display with its speedometer-like
appearance (displaying the respiratory volume in %) makes it possible to easily read and
understand the measured values, even for children under the age of 6 years.
Fig. 1: Sensor base made of plastic with sensor structures made by
electrodeposition. At first, the entire surface exhibits sensor activity;
in a further step, the sensor capacity on the surface in the area of the
layout struc-ture is deactivated by applying a gold layer.
86
Fig. 2: The „Lufttacho“ is a medical device for children suffering from asthma
comprising a gas mass flow sensor
made of plastic.
Publications
A. Scholz, J.M. Herrmann, B. Wolf, „Etablierung neuer Therapiekonzepte durch den
Einsatz von Telemetric Personal Health Monitoring Systeme“, DGBMT 2004., Berlin, pp.
256-257.
A. Scholz, V. Lob, J. F. Clauss, J. M. Herrmann, B. Wolf: „Einbindung von Sensorsystemen
in das TPHM-System“, Biomedizinische Technik Vol. 49, pp. 224-225, 9/2004.
B. Wolf, A. Scholz, J.M. Herrmann, „Mikroelektronische Sensoren als Schlüsselbauelemente für telemetrische Healthcare Systeme“, Biomedizinische Technik Band (Vol.) 49, pp.
400-401, 9/2004.
J. Eberspächer, A. Picot, G. Braun, „eHealth: Innovations und Wachstumsmotor für Europa“ Kapitel (chapter) 18, pp. 261- 268, Springer 2005.
A. Scholz, B. Hörnler, A. Djermester, J. Clauss, B. Wolf, „Physikalische Limitierung für
Flussmessung im Anwendungsfall der Spirometrie“, 6. Würzburger Medizintechnik Kongress, pp. 356-357, 5/2005.
H.-G. Gruber, A. Scholz, J. Clauss, B. Wolf, „Mobile Telemedicine Systems and Their
Effects on the Medical Value Chain and new Business Models“, European Academy of Management EURAM2005 5th Annual Conference Preceedings, p.65, www.euram2005.org
Project title: „GaSeMed“ -Einweg-Gasfluss-Sensor für medizinische Anwendungen“ („GaSeMed” - disposable gas flow sensor for medical applications)
Project life span: 1 March 2008 to 28 February 2012
87
New therapeutic options with COMES®
In view of the fact that age-related diseases such as cardiovascular disorders, primary hypertension, diabetes, heart failure or stroke are on the rise, a team at our faculty is working
on a systemic care approach for patients suffering from these diseases. In this context,
the Cognitive Medical System (abbreviated to COMES®) developed in this project plays
quite an important role.
COMES® is a new mobile diagnostics and therapy platform that offers patients the possibility to lead a healthy and independent life. It has resulted from various development projects involving sensor-enabled systems during the past ten years, and helps to measure,
transmit and verify biomedical data by means of established measuring techniques and
communications structures [1,2].
COMES® was conceived in the middle of 2009 with the support of the companies Synergy
Systems GmbH and Pasife GmbH. Since November 2010, COMES® has been funded by
Heinz Nixdorf Stiftung as part of the „Kompass“ project and is being gradually expanded
and modernised. Our aim with COMES® is to enable medical diagnostics and intervention
at any time, anywhere. To this end, intelligent databases are used as an important support
system for individualised therapy and follow-up – and for motivating the patient.
Thanks to the use of modern databases, physicians can offer personalised information or
establish a dialogue with a particular patient.
A wide variety of sensors – some of which were developed at our faculty – are already
available for the COMES® system. Not only can patients measure their blood pressure, weight and activity in a familiar and comfortable environment, but values relating to
diabetes, bruxism, breathing volume and breathing-related sleep disorders can also be
monitored. The data thus obtained are then automatically transmitted via smartphone to
the COMES® Trust Center, while guaranteeing compliance with the applicable data safety
standards. The patient may further complete questionnaires directly on his/her smartphone, tablet PC or computer and provide additional information useful to his/her physician
that can be stored in the system.
We are currently doing research into the following points: user acceptance, expansion of
the feedback system, application of personalised motivation methods.
[1].B. Wolf, „Einrichtung zur Früherkennung von kritischen Gesundheitszuständen, insbesondere bei Risikopatienten“. Offenlegungsschrift (patent application document No.) DE
100 06 598 A 1, DPMA (German Patent and Trademark Office), 2001.
[2].B. Wolf, P. Friedrich, S. Becker, J. Clauss, D. A. Hofsøy, A. Scholz, „Ambient Medicine® sensorge-stützte Assistenzsysteme für die telematische Diagnose und Therapie“,
e-Health2010 Informations-technologien und Telematik im Gesundheitswesen / Frank
Duesberg (Hrsg.), Solingen, pp. 230-236, 2010.
88
Fig. 1: The complete COMES® system
Fig.2 Measuring devices connected to
COMES®
Publications
T. Spittler, P. Friedrich, B. Wolf: Smartphone-Schnittstellen für telemedizinische Anwendungen, ntz Heft 1/2011, S. 38-41
T. Spittler, P. Friedrich, B. Wolf: COMES® - ein zukunftsweisendes telemedizinisches Assistenzsystem; in: Heinz Nixdorf Symposium Bioelektronische Diagnose- und Therapiesysteme. München, Heinz Nixdorf-Lehrstuhl für Medizinische Elektronik, 2010, S. 161-162.
This research was funded by the Heinz Nixdorf Stiftung, the Synergy Systems GmbH and
the Pasife GmbH.
Project title: COMES® – „Cognitive Medizinische Systeme“ (COMES® – Cognitive Medical
Systems)
Project life span: 1 September 2009 to 31 August 2012
89
KOMPASS – „Kognitives Medizinisches Personalisiertes Assistenzsystem” (Cognitive medical personalised assistance system)
The project entitled „Development, evaluation and optimisation of a telemedical assistance system for prevention, diagnosis and therapy“ was initiated and conceived by our
department to investigate the use of cutting-edge sensors combined with communications and information systems. This work is being done in cooperation with the Heinz Nixdorf Institut of the University of Paderborn (Professor Ordinarius: Prof. Dr. Jürgen Gausemeier). Our aim is to promote the use of microelectronic and telematic systems in medical
research but also in practical medicine, and to enhance their performance.
The aim of the „KOMPASS“ project is to deliver a demonstrator for a telemedical assistance system for prevention, diagnosis and therapy, comprising a sensor system along
with a data transmission and processing system. This technology may be used for improving patient care, especially with a view to the growing phenomenon of an ageing society
and an increasing shortage of physicians. We expect that evidence-based telemedical
interventions may help to reduce the costs of public healthcare.
In this context, we are working on optimising the sensor systems developed in the COMES® project and on evaluating them by conducting studies and test phases involving
patients in hospitals and rehabilitation clinics, as well as private individuals in specific,
selected environments.
Fig. 1: A part of the COMES® platform
consisting of a step counter, a wrist
sphygmomanometer, a blackberry telephone with Bluetooth and the COMES®
Web Frontend
90
COMES®, an intelligent assistance system for delivering personalised therapy concepts,
is the technical basis for our mobile diagnosis and therapy platform (see article 33). In a
similar way to other expert systems, it enables a user‘s individual medical data to be merged with those stored in higher-level databases and can provide personalised information
or intervene directly, if necessary.
The experience gained in user tests during our research will be used for creating new
diagnosis and therapy concepts. Thanks to the additional combination of sensor systems
with information and communications technologies, we are able to facilitate targeted and
individual monitoring of vital parameters.
A further important part of this project is to develop an appropriate business model which
should reveal how potential benefits can be exploited and how the system may be operated economically in the long run.
Fig. 2: Besides a healthier lifestyle, the
innovative assistance system also offers
active involvement of the patient in the
therapeutic and recovery process.
This ongoing research project has been funded by the Heinz Nixdorf Stiftung.
Project title: „Entwicklung, Evaluation und Optimierung eines telemedizinischen Assistenzsystems zur Prävention, Diagnostik und Therapie“ (Development, evaluation and optimisation of a telemedical assistance system for prevention, diagnosis and therapy)
Project life span: 1 November 2010 to 31 October 2013
91
KoKeTT – the AAL test and training centre in cooperation with Hochschule Kempten
The AAL Anwenderzentrum KoKeTT (AAL User Centre KoKeTT) was founded in the autumn of 2011 as part of a joint venture with the Hochschule Kempten. KoKeTT stands for
KOMPASS Kempten Test- und Trainingszentrum (KOMPASS Kempten Test and Training
Centre) and is a joint project with the Heinz Nixdorf-Lehrstuhl für Medizinische Elektronik of Technische Universität München. Based on the research and teaching discipline
„Grundlagen der Elektrotechnik und Ambient Assisted Living (AAL)“ (Fundamentals of
electrical engineering and Ambient Assisted Living (AAL)) which forms part of the university course for mechatronics, AAL is an area of specialisation whereby KoKeTT represents
the first AAL application centre for healthcare in the Allgäu region (south-western Germany). It provides students with a practical and project-based education.
Both research institutions are working closely together on this topic. We have therefore
come to the conclusion that the application-oriented problems arising with the KOMPASS
project (Kognitives Medizinisches Personalisiertes Assistenzsystem) at the Heinz NixdorfLehrstuhl für Medizinische Elektronik should be studied intensively at a specifically equipped laboratory of the Hochschule Kempten. The aim of KoKeTT is to test the systems
developed at Technische Universität München in cooperation with existing and new user
groups for their practical usability. In this context, KoKeTT can be used by all medical
institutions intending to employ personalised assistance systems with modern information
and communications technology or requiring support in the use of these sys-tems.
KoKeTT enables the testing of practically oriented therapy management systems for
conditions such as diabetes, obesity, cardiovascular diseases and psychosomatic disorders, as well as for patients who require rehabilitative care. For this purpose, the test and
training centre is equipped with various telematic measuring systems, providing different
configuration options and allowing for different settings according to the different ICT
infrastructures of medical institutions. Landline and mobile communications-enabled
analysis and therapy platforms can be used, by means of which problems such as telemonitoring and the development of personalised telematic therapy structures may be
addressed. Together with KoKeTT, potential users may develop suitable test scenarios,
enhance existing equipment and also perform on-site tests of new diagnostic and therapeutic systems.
Users of all ages may therefore test new technical solutions and therapeutic concepts.
These include rehabilitation clinics, business users, senior researchers (70+), as well as
medical practitioners. Further, AAL products are tested for feasibility, usability and ergonomics, and for technical or clinical characteristics. KoKeTT can also be used by the
elderly and their relatives if they wish to fully test a desired product or solution prior to
purchase.
The foundation for this test and training centre is a cooperative agreement made by the
Heinz Nixdorf-Lehrstuhl für Medizinische Elektronik and Hochschule Kempten.
92
Fig. 1: From innovative therapeutic concept to user test
Fig. 2: From user test to market
The AAL Anwenderzentrum KoKeTT (AAL User Centre KoKeTT) was founded in the autumn of 2011 as part of a joint venture with the Hochschule Kempten. KoKeTT stands for
KOMPASS Kempten Test- und Trainingszentrum (KOMPASS Kempten Test and Training
Centre) and is a joint project with the Heinz Nixdorf-Lehrstuhl für Medizinische Elektronik
of Technische Universität München.
93
Development of a personalised pedal exerciser [PREAM - Prevention and Rehabilitation through Activity and Motivation]
Many elderly persons suffer from disease-related mobility impairments that lead to a lack
of flexibility and above all a lack of activity. There are many possible causes, including
cardiovascular diseases, rheumatism, arthritis, as well as the consequences of a stroke or
a fall.
In this context, a sufficient amount of activity is still important and makes therapeutic
sense. As a solution to this problem, we have developed a telemedical pedal exerciser
connected to a conventional television set via a DVB-T set-top box. The system enables
users to continue their exercise at home after returning from a rehabilitation clinic, or prevent oedema or thrombosis, simply by doing pedalling exercises. The exercise programme is complemented by individually adapted background information, and exercise and
motivational instructions provided through the TV set that are easy to follow. Feedback on
the distance covered and the energy consumed (calories burned) is displayed constantly
on the TV screen. The project aims to integrate further telemedical services.
We have succeeded in configuring the sensors of the pedal exerciser and its wireless link
using the wireless standard ANT and the profiles ANT+ with the DVB-T set-top box, and
have thus developed a cost-effective pedal exerciser called iBikos which is suitable for
therapeutic use at home. We have also developed a concept for monitoring the amount
and intensity of activity
Fig. 1: Integration of the therapeutic
exerciser into the telemedical assistance system COMES® (image source:
Pasife GmbH)
94
Fig. 2: iBiKos, the telemedical exerciser,
offers an entertaining activity and health
programme (image source: Pasife
GmbH)
Fig. 3: Diagram of data transmission
Microcontroller
ANT + Bike Power
Receiver Profile
Channel 0
ANT + Bike Power
Transmitter Profile
Channel 0
Sensor
system
ANtap1M51B
Pedal exerciser
set-top box
shared memory
ANT wireless
ANT + Bike Cadence
Transmitter Profile
Cannel 1
from the pedal exerciser to the DVB-T
ANT + Bike Cadence
Receiver Profile
Cannel 1
ANT USB1 Stick
STB7743
This research was funded by the Bayerische Staatsministerium für Wirtschaft, Infrastruktur, Verkehr und Technologie.
Project title: „PREAM - Prävention und Rehabilitation durch Aktivität und Motivation“
(PREAM - Pre-vention and Rehabilitation through Activity and Motivation)
Project life span: December 2009 to December 2010
95
iBikos II - Development of a telematic rehabilitation exerciser as an integrated home
care product
The iBikos II project is a logical advancement to the system developed in the PREAM project. While the iBikos I exerciser is a low-cost version and is connected with the TV set in
the user‘s home via a set-top box, the iBikos II incorporates the latest level of technology:
it is based on a sophisticated therapeutic exerciser, the Bluetooth-enabled device Theravital of Medica Medizintechnik GmbH. The design is compatible with the latest generation
of Internet-compliant television sets.
A system has been developed that comprises a telematic rehabilitation exerciser, a plug
computer for mains operation and real-time animation, and was conceived with the idea
of potentially expanding the COMES® telemedical assistance system.
Based on the live data recorded by the exerciser in real time, we have implemented receiver software in Java for the plug computer. This software screens the data received via a
Bluetooth interface and transmits them to a database. These data are then converted by
the web animation system into a racing game and displayed on a the TV screen, partly
superimposing the current image. The idea is that the remaining picture may be a TV or video image, or a Skype window, and that - thanks to the web-based concept - the remote
device merely needs a browser (e.g. Smart TV) to enable the display.
For increased motivation, the user exercises in front of the TV set while the captured data
are visualised in an interactive display.
The captured training data are not only shown on the TV screen, but are also stored in a
database system which is intended to be incorporated into the COMES® database. The
results are evaluated by a physician who then returns them to the patient in the form of a
message along with recommendations for further exercise. What motivates the user is not
only his/her growing ambition during training, but in particular the long-term overview of
the amount of exercise accomplished, as well as the professional feedback given by the
physician. This allows new goals to be set and ensures consistent training.
Using the Bluetooth-enabled Thera-vital device and linking it with the COMES® platform,
we have created a system that provides an all-round picture of the current state of health
of a patient at any time. The physician can use this information to determine the achievable scope and make training recommendations.
Fig. 1: Cycle race web animation with
the user playing the role of the black
Current Speed
cyclist , and two opponents.
10,7 pm
Player
Opponents
Remaining time +
Distance to Opponents
Training time : 00:16:25
Red ( 40 rpm ) +2 m
Purple ( 50 rpm ) +7 m
96
Fig. 2: Idea and procedures during a
Motivation
training session at home
Demograpgy
high TV
consume
little activity
Publications
K.-U. Hinderer, „Entwicklung eines telemedizinischen Bewegungstrainer als Home Care
Produkt“, Diplomarbeit am Heinz Nixdorf-Lehrstuhl für Medizinische Elektronik der Technischen Universität München, 2012
K.-U. Hinderer, P. Friedrich, B. Wolf, „Home Care: A Telematic Rehabilitation Exerciser“,
IEEE Second International Conference on Consumer Electronics, 2012, Berlin, pp 13-18,
978-1-4673-1547-0/12.
This project was initiated in the autumn of 2011 and is a joint venture with Hochschule
Kempten
97
Diabetes management from a student‘s viewpoint – the project
„DiaManTUM“
Diabetes mellitus is one of the most common metabolic diseases in western industrialised
nations, with approximately 90% of patients suffering from type II and approximately 5%
from type I diabetes. With over 8 million diabetes patients in Germany and an estimated
246 million diabetes patients worldwide, this disease has become one of the most widespread diseases in industrial nations of the west.
Besides the primary symptoms such as permanently increased blood glucose levels, diabetes entails the risk of constricted arteries and thus a significantly increased risk of myocardial infarction and stroke. Therefore, therapy focuses not only on correcting the blood
glucose level, but also on managing the blood pressure, blood lipids and other disorders.
Since the beginning of 2011 this topic has been investigated by the DiaManTUM project,
which is financed by tuition fees. A project team consisting only of students is working on
the individual modules.
The aim of DiaManTUM is to help diabetes patients manage their condition. The telemedical assistance system COMES® is being used during this project. Via a platform, COMES®
users may measure and record their individual parameters (here the blood glucose level)
– without the assistance of a doctor, hospital or other care provider – by means of the
certified COMES® measuring devices. In an easy, fast and reliable way, the measured
values are transmitted to the COMES® Data Centre; the patient receives prompt feedback
from the medical expert centre or – as an option – directly from a general practitioner sent
to his/her personal mobile phone.
The DiaManTUM project team has designed and developed a „glucose stick“ the size of a
USB memory stick as a prototype. This device allows the blood glucose level to be measured and the acquired data to be transmitted via a serial USB connection or via mobile
communications to a smartphone, ultimately reaching the COMES® Trust Centre.
Measuring the blood glucose level is not the only important aspect of diabetes management, however. An appropriate diet and adequate exercise also play an important role. We
are therefore working on a system that can record the approximate number of carbohydrate units consumed by a patient using a smartphone. It should also be possible to make
meal suggestions and provide the corresponding recipes or a shopping list. At the present
stage of the project, it is possible to use the COMES® device to capture exercise data and
provide the user with feedback as well as the motivation to keep exercising.
Since 2011, this ongoing research project has been financed by tuition fees of Technische
Universität München.
Project title: DiaManTUM
98
Fig. 1: Glucose stick (size of a USB stick) with mobile phone
99
Appendix
Innovationszentrum – Spin-offs
The expertise at our Innovationszentrum Medizinische Elektronik e.V. includes, among
others, intelligent implants, Ambient Medicine® and cell-based systems. IME e.V. is a non
profit organisation.
The company sendsor GmbH develops Telemetric Personal Health Monitoring (TPHM)
systems: miniaturised medical devices that differ from conventional sensor systems by
actively involving the patient in the therapeutic concept.
The key business of Ambright GmbH, a company focusing on intelligent, industry-specific lighting solutions, is the development of multi-purpose LED lights and accompanying
control units. In cooperation with Heinz Nixdorf-Lehrstuhl für Medizinische Elektronik, the
company is working intensively on the design of optical biofeedback systems as therapeutic lighting solutions in medical practice.
The company cellasys GmbH offers cell-based systems for continuously monitoring the
vitality of living cells. These systems comprise on the one hand the requisite hardware and
consumables such as biohybrid sensor chips, and on the other hand the necessary software components for data management and interpretation as well as consultation in the
field of cell-based systems and their application.
Bionas GmbH is a spin-off based on the long-standing collaboration between Prof. Bernhard Wolf and semiconductor manufacturer Micronas AG at its subsidiaries in Freiburg im
Breisgau and Rostock. The company‘s products are the result of the basic research work
done by Prof. Bernhard Wolf‘s teams.
100
Facilities
101
Faculty lectures, workshops and events
102
Events
Location
Year
Continuous lectures of the Arbeitskreis
Medizintechnik & Lifescience Electronic
(Study group medical device technology &
life science electronics)
in cooperation with the VDE (Verband
Deutscher Elektrotechniker)
Elektronik , Munich
Since 2005 (please visit
www.lme.ei.tum.de)
Symposium:
Individualisierte Chip-basierte Chemosensitivitätstestung (Individualised chip-based
chemosensitivity testing)
Bayerisches Staatsministerium für Wirtschaft, Infrastruktur, Verkehr und Technologie,
Munich
3 June 2005
1. Omron / Heinz Nixdorf Ambient Medicine® Symposium
Technologiezentrum Bernried / Starnberger See
14 October 2005
Workshop Herbstuniversität – Mädchen
machen Technik (Autumn college workshop – Girls do tech): „Mit dem iPod
therapieren“ (iPod therapy)
Elektronik, Munich
2-4 November 2005
IBM on Campus IBM Deutschland Entwicklung GmbH
Technische Universität München
2 December 2005
m3 Symposium: microelectronic meets
medicine (m3)
Bayerisches Staatsministerium für Wirtschaft, Infrastruktur, Verkehr und Technologie
Munich
22 June 2006
machen Technik: „Der Arzt im Gepäck: Elektronik für die Gesundheit” (Autumn college
workshop – Girls do tech: „A doctor always
at hand: Electronics for your health“)
Elektronik, Munich
29-31 October 2007
CeBit Future Talk „Unsere Zukunft in IKT“
(„Our future in ICT“)
Congress of the D21 Initiative
Hannover
8 March 2008
Events
Location
Year
Symposium:
„Tools for Tissue Engineering“
Zentralinstitut für Medizintechnik der TU
München / Garching
11 April 2008
Life Sciences live at
IMETUM
Open day
München / Garching
13 June 2008
Special Seminar: Prof. Dr. G.W. Gross:
NEUROENGINEERING – Emerging Concepts and Challenging Applications
München / Garching
27 June 2008
1. Workshop of the ITG FA 9.3. Biomedizinische Informationstechnik (Biomedical
information technology)
München / Garching
5 November 2008
Interdisziplinäres Diskussionsforum: System-Medizin „Wider den Methodenzwang“
- Systemische Ansätze für neue Therapieformen (Interdisciplinary discussion forum:
Systems medicine „Against methodological constraints“ - Systemic approaches to
new forms of therapy)
Semper-Sternwarte, Zurich
25 March 2010
3. Ambient Medicine® Forum
Klinik Höhenried, Bernried
22 June 2010
Heinz Nixdorf Symposium 2010 m3: microelectronic meets medicine
Bioelektronische Diagnose- und Therapiesysteme (Bioelectronic diagnosis and
therapy systems)
Business Center der BMW Welt
Event Forum
Munich
12-13 October 2010
Senior Research Day 2011
Elektronik, Munich
13 April 2011
103
Events
Location
Year
machen Technik: „Hands-On Streifzug
durch den Lehrstuhl“ (Autumn college
workshop – Girls do tech: „Hands-on
excursion: exploring the faculty“)
Elektronik, Munich
3 November 2011
4. Ambient Medicine® Forum and Statuskolloquium zum Forschungsprojekt KOMPASS (Status colloquium on the research
project KOMPASS)
Schloss Höhenried, Bernried
26 April 2012
Awards
Award winner/topic
Year
Praxis-Depeschen Award
Dr. Alexander Scholz,
Prof. Bernhard Wolf
2004
Alfred Kärcher-Förderpreis
Bernhard Gleich, „Sensorentwicklung”
(Sensor development)
October 2005
IFMBE Young Investigator’s Award,
7th International Conference on Cellular
Engineering
Dr. Johann Ressler,
„24-well microplate with sensors for metabolic, morphologic and electrophysiologic
parameters of living cell tissue”
September 2005
ABRF Award,
Association of Biomolecular Resource
Facilities
Dr. Jochen Peter
April 3, 2007
HUPO Young Investigator’s Award,
The Human Proteome Organization
Dr. Jochen Peter
„Proteomic Sciences”
October 2007
Honours and Awards
104
Awards
Award winner/topic
Year
E.ON Umweltpreis (E.ON Environmental
Award),
E.ON Bayern
Elektronik der Technischen Universität
München,
„Wasserqualitätsmonitoring mit biohybriden Sensorchips“ (Water quality monitoring with biohybrid sensor chips)
July 22, 2008
DGBMT Preis 2009,
Deutsche Gesellschaft für Biomedizinische
Technik im VDE
Dr.-Ing. Joachim Wiest,
„Entwicklung und Erprobung von miniaturisierten, elektrochemischen Sensoren
für die Gelöst-Sauerstoff-Messung zum
Einsatz in Lab-on-Chip Systemen“ (Development and testing of a patient-specific
tumour chemosensitivity test based on a
silicon sensor chip)
September 11, 2009
Mitgliedschaft Deutsche Akademie der
Technikwissenschaften (Membership of
the National Academy of Science and
Engineering)
Professor Dr. Bernhard Wolf was admitted
to the Deutsche Akademie der Technikwissenschaften
October 20, 2009
Best Poster Award / ibai, Industrial Conference on Data Mining
Dipl.-Ing. Thomas Spittler,
„COMES® - ein telemedizinisches Assistenzsystem zur Früherkennung von
Depression bei Herzinsuffizienz“ (COMES®
- a telemedical assistance system for the
early detection of depression in patients
with heart failure)
August 2011
Münchner VDE-Award 2011
Dr. Joachim Wiest,
Erfolgreiche Firmengründung der cellasys
GmbH (Successful establishment of the
company cellasys GmbH)
November 2011
105
List of researchers
Research professor
Wolf, B.
Research associates
Grothe, H.
Brischwein, M.
Clauss, J.
Neumann, B.
Herzog, K.
Friedrich, P.
2004-2011
Otto, A.M.
Gleich, B.
Weyh, T.
Rampf, R.
Pilawa, P.
Peter, J.
2001-2010
2007-2010
2001-2009
2001-2003
2001-2004
2005-2009
Schlichting, H.
Renger, J.
Ninichuk, V.
Janas, E.
Dahmani, C.
Götz, S.
2002-2004
2003-2004
2010
2010
2007-2010
2008-2010
Teschner, G.
Szabados, I.
Wankerl, B.
Zirm, W.
2000-2011
2005-2007
2007-2009
2000-2001
Research staff
Arbogast, R.
Ruppert, W.
Giorno, A.
Remm, M.
Michelfelder, A.
Franz, I.
Toldrian, J.
Stein, S.
Sawatzki, J.
Kaneppele, A.
External assistants
Wolf, P.
Lachner, A.
Doctoral candidates
Aicher, M.
Barthel, J.
Demmel, F.
Dill, D.
Eminaga, Y.
Gattinger, N.
Grundl, D.
Gül, M.
106
Häcker, M.
Hafner, L.
Ilchmann, F.
Janzon, C.
Kleinhans, R.
Mengele, A.
Mzoughi, N.
Pfister, C.
Sattler, M.
Schwarzenberger, T.
Spittler, T.
Türmer, C.
Weber, A.
Weiß, R.
Wirths, W.
Zottmann, M.
Doctoral theses
Henning, T.
Studien zur Entwicklung eines prädiktiven Chemosensitivitätstests mit Mikrosensoren
2002
Koch, M.
Nicht invasiver Transport von Ladungsträgern in komplexen Materialien
2004
Motrescu, E.
Analysis of Biological Signals with Multifunctional Bioelectronic Sensor Chips on
Living Cells
2004
Stepper, C.
Entwurf, Herstellung und Charakterisierung von Biosensorchips
2005
Cabala, E.
Monitoring multiparametrischer komplexer Mikrosensorarrays für zelluläre Analytik
2007
Gleich, B.
Aktiver Wirkstofftransport mit magnetischen Feldern
2007
Geisler, T.
Echtzeitumgebung (Hard- und Firmware-Plattform) für ein Mikroskop-basiertes
„Machine-Vision“ System
2007
Wendicke, K.
Optimierung von Stimulationsspulen für die induktive Nervenreizung
2007
Zantow, H.
Optimierung des Strom-Zeitverlaufs für die Depolarisation von Nervenzellen
2007
Stadthagen, T.
Entwicklung eines online Gewässermonitoringsystems mittels Biosensorchips zum
Nachweis ausgewählter Xenobiotika
2007
Amaral, C.E.F.
Multiparameter Methods for Non-invasive Measurement of Blood Glucose
2008
Wiest, J.
Entwicklung und Erprobung von miniaturisierten, elektrochemischen Sensoren für
die Gelöst-Sauerstoff-Messung zum Einsatz in Lab-on-Chip-Systemen
2008
Reßler, J.
Sensorchips für die multiparametrische zelluläre Bioanalytik und für biohybride
Bauelemente
2008
Lob, V.
Design und Realisierung eines High-Content-Screeningsystems für lebende Zellen
2009
Friedrich, P.
Etablierung einer telemedizinisch gestützten bioakustischen Hypertonie-Therapie
mittels Virtual Lab
2010
Meyer, J.
Evaluation of new bioelectronic cell based assays for diagnostic and therapeutic
systems
2010
107
Scholz, A.
Konzepte für eine personalisierte telematische Medizin
2010
Gruber, H.-G.
Telemonitoring-Systeme: Gesundheitsökonomische Evaluation und Innovationsbarrieren
2011
Schmidhuber, M.
Konzeption und Erprobung eines biohybriden nanoanalytischen Handheld Systems
2011
Clauss, J.
Intelligente Zahnschiene als Technologieplattform für sensorische Implantate
2011
Becker, B.
Automatisierung eines Cell-Based-Assay Systems zur prädikativen Tumourklassifikation
2011
Becker, S.
Intelligente Implantate zur Therapieunterstützung
2011
Hofsøy, D.A.
Development and evaluation of a long-term management system for sleep-related
breathing disorders
2011
Bahr, L.
Evaluierung planarer Sensorstrukturen zur Messung der Zellulären Respiration
2002
Neurauter
Optisch plethysmographische Signale
2002
Rinser, M.
Image Processing for Automated Measurement and Analysis of Cardiac function in
Drosophila Melanogaster
2002
Scholz, A.
Bluetooth-Anbindung von Biomodulen zur Messdatenübertragung
2002
Steinmann, M.
Entwicklung einer Microcontroller-Steuerung mit CAN-Schnittstelle für einen magnetischen Neurostimulator
2003
Wiest, J.
Measurement of pH and pO2 change at an ISFET surrounded by a noble metal
electrode
2003
Loeser, M.
Behavior of polarizable micro-particles in inhomogeneous fields
2003
Schmidt, M.
Sensorarray for fetal ECG signals: simulation, sensor selection and source separation
2003
Diploma theses
108
Ressler, J.
Entwicklung und Evaluierung von impedanzsensorgestützten Multiwellplatten zum
zellulären Screening
2003
Holzinger, S.
Entwicklung und Aufbau eines biohybriden Monitors für Regenwasserqualität
2003
Gneiting, S.
Entwicklung eines röntgenbasierten 3D-Hüftprothesen-Planungssystems
2003
Cabala, E.
Neuentwicklung von Software für ein multiparametrisches Meßsystem
2003
Kang, S.H.
Evaluierung eines nicht-invasiven Impedanzsensors zur Hydratationsmessung der
Haut
2003
Fuchs, C.
Analyse und Implementierung ausgewählter Rauschunterdrückungsmethoden zur
Anwendung bei optisch plethysmograyhischen Signalen
2003
Slusarczyk, M.
Optimisation of the power circuit of a magnetic neurostimulator
2003
Erl, T.
Entwicklung und Evaluierung analoger Messelektronik für ein LAPS-basiertes pharmakologisches Mehrfachtestgerät
2003
Lob, V.
Entwicklung eines Telemetric Personal Health Monitoring Systems für Bluthochdruckpatienten
2003
Gleich, B.
Entwurf und Dimensionierung eines EMG Messsystems
2004
Pelhak, S.
Sicherheitsfunktion für Magnetstimulator - metal detect
2004
Wagner, R.
Entwicklung und Realisierung der Steuerung und der PC-Schnittstelle für ein optoelektronisches pH-Meßsystem
2004
Kotzlowski, S.
Entwicklung und Integration einer mikrocontrollerbasierten Ethernetschnittstelle für
biomedizinische Messsysteme
2004
Holbein, N.
Entwicklung einer Mikrocontrolleranbindung und Verbesserung von Messelektronik
für impedanzsensorgestützte Mikrotiterplatten
2004
Clauss, J.
Telemetrisches Diagnose- und Therapiesystem für Schlafstörungen
2004
Schnitzler
Durchschussdetektion und Steuerung eines Laserprozesses bei der Produktion von
Patch-Clamp-Chips
2004
109
110
Seidl, N.
Magnetic Drug Targeting
2004
Herzog, T.
Charakterisierung von Dickschichtsensoren für pH-Wert, elektrische Impedanz und
Sauerstoff
2004
Christ, B.
Entwicklung eines multiparametrischen Sensorsystems zum Monitoring von
Adipositas
2005
Beckler, M. J.
Entwicklung einer pneumatischen Pumpe und ihr Einsatz in mikrofluidischen
Systemen
2005
Veyrat, A.
Automatic Image Fusion of Pre- and Intraoperative Patient Data. Statistical Evaluation of Accuracy
2005
Meyer, J.
Magnetic Stimulation of Neuronal Cell Cultures
2005
Huber, F.
Telemetrisches Diagnose- und Therapiesystem für Asthmatiker
2005
Schmidhuber, M.
Design eines Messplatzes zur mobilen Analyse von lebenden Zellen für medizinische Diagnostik und Umweltanalytik
2005
Blau, A. S.
„White Border“ Artefakt-Unterdrückung in Mammographie-Aufnahmen in der digitalen Röntgen-Diagnostik
2005
Menard, P.
JiMIC, an ImageJ Plugin for the iMIC microscope
2005
Dirscherl, A.
Einsatz digitaler Signalprozessoren in der bioanalytischen Messtechnik
2005
Iwainsky, S.
Analyse von Verfahren zur vollautomatischen Segmentierung von Zellkernen
2005
Hahn, M.
Analysis of Motion Data Allows Preventative Maintenance in Robotic Arms
2005
Probst, A.
Bruxismus Biofeedback
2005
Gerber, M.
Vergleich verschiedener Highside-Treiber-Topologien für IGBTs
2005
Rwebugisa, W.
Untersuchungen zu Messtechnik und Monitoring gesundheitsschädlicher Nanopartikel und Gase in der Atemluft
2005
Ebert, M.
Nachweis von Nanobeads in Fluiden mittels Microbalance
2006
Ilchmann, F.
Optimierung einer sensorgestützten Testplattform zur Durchführung multiparametrischer Messungen an elektrisch aktiven Zellen
2006
Frech, A.
Entwicklung eines neuen Frequency-Domain Nahinfrarotspektroskopie-Gerätes mit
FPGA Softcore
2006
Streibl, S.
Redesign und Aufbau eines Messplatzes für multiparametrische Sensorchips
2006
Tiefenthaler, T.
Mobile Einsatzmöglichkeiten der magnetischen Neurostimulation
2006
Becker, S.
Development of a Sensor System for Identification of Persons using Acceleration
2006
Djermester, A.
Algorithmenentwicklung zur Spurwechselunterstützung
2006
Grundl, D.
Konzeptionierung und Entwicklung eines Hochdurchsatzsystems zur Kalibrierung
multiparametrischer Keramiksensoren
2006
Blank, S.
Finite Elemente Modellierung und experimentelle Validierung der physikalisch-chemischen Prinzipien biohybrider Mikrosensoren
2006
Brückl, M.
Korrelation der Impedanz-Änderung einer interdigitalen Elektrodenstruktur mit dem
Wachsen oder Absterben von Zellen auf der Struktur
2006
Karg, M.
Evaluation and Sotware Development for the Sensor-Integrated MEA Chamber &
Robotic Maintenance for Nerve Cell Chambers
2006
Füeßl, F.
Datenmanagement für personalisierte, medizinische Sensoren
2006
Hebebrand, M.
Investigation of wavelength dependence of Optical Coherence Tomography imaging
using swept sources
2006
Benning, D.
Development of a basic human circulatory control model and the influence by the
auditory cortex via music
2006
Milling, J.
Modulare Realisierung von Betriebskomponenten eines „intelligent mobile lab“Systems
2006
Tröbersberger, M.
Entwicklung einer mehrphasigen Spulenansteuerung für magnetischen
Zell-Transport
2006
Krid, H.
Nichtinvasive Glukose-Messungen
2006
111
112
Heinz, A.
Entwicklung einer Interventionsstrecke für ein automatisiertes Biofeedback auf Basis
des TPHM-Systems
2006
Gül, M.
Optmierung einer Pipettierrobotersteuerung mit integrierter Schrittdetektion
2006
Schiopu, D.
RuO2 als pH-Sensormaterial für biomedizinische Anwendungen
2006
Hoke, K.
Untersuchungen zur Verbesserung der Stabilität voltammetrischer O2-Sensoren in
physiologischen Medien
2007
Stengel, T.
Verstärker und Datenerfassungssystem für die parallele elektrophysiologische Charakterisierung von Zellen
2007
Franzke, M.
Konzept und Entwicklung eines Low-Cost-Screeners zur Feststellung
schlafbezogener Atemwegsstörungen.
2007
Dill, D.
Digitale Bildverarbeitung für die Mikroskopie
2007
Gheorghe, C.
Entwicklung eines Kalibrierungsfreien Spirometers
2007
Malik, H.
Impedance Spectroscopy applied to Blood Clotting Methods
2007
Messmer, A.
Ermittlung und Erprobung eines Virtual Labs auf TPHM-Basis am Beispiel der essentiellen Hypertonie
2007
Meng, L.
Kapazitive Tastaturen
2007
Gharbi, A.
Piezoelektrisch-basiertes Sensor-Aktor-System zur Messung von Kräften und zur
mechanischen Stimulation
2007
Becker, B.
Integration des IMWP-Systems mit C++ und XML
2007
Sattler, M.
Entwicklung eines implantierbaren Sensorsystems zur Überwachung der
Knochenheilung
2007
Israel, M.
BioChip-Impedanzspektroskopie / Entwicklung eines Impedanzmessgerätes auf
Basis des AD5933
2007
Humiao
Kraftwirkung dynamischer Magnetfelder auf gelöste Ionen
2007
Poppe, M.
Verifikation und Aufbau eines Sensors für Realisierung pulsoximetrischer Messungen am Handgelenk
2007
Turki, Y.
Vermessung und Erprobung verschiedener Isolationsverfahren biokompatibler
Sensorchips
2007
Fan, Xiaoqian
Impedanzanalyse an bioelektronischen Mikrotiterplatten
2007
Zauner, Peter
Fahrerbeanspruchungsanalyse und Notfallerkennung mittels biomedizinischer
Vitalparameter
2007
Baumann, D.
Entwicklung einer Aktivitätskarte
2008
Ketzer, S.
Development and Verification of a Three Dimensional MRI Receive Coil Array for
Improved B1-Homogeneity
2008
Federsel, T.
Entwicklung und Realisierung einer High-Side Hochspannungs-IGBT Ansteuerung
2008
Eminaga, Y.
Characterization of miscellaneous multi parametrical silicon based biosensor chips
2008
Zhang, C.
Entwicklung einer parallelen Ableitungsplattform zur Durchführung multiparametrischer Messungen an elektrisch aktiven Zellen
2008
Kibler, S.
Software Implementierung der Vitalparametrerfassung für Fahrerbeanspruchungsanalyse und Notfallerkennung
2008
Hoke, I.
Simulation einer Magnetanordnung zur Retention magnetischer Nanopartikel im
Gehirn einer Versuchsmaus
2008
Radrich, K.
Reconstruction of an in silico metabolic model of the plant Arabidopsis thaliana
2008
Hensle, S.
Entwicklung einer grafischen Benutzeroberfläche für ein
High-Content Screeningsystem
2008
Gläßner, J.
Untersuchung des Partikelverhaltens in den Atemwegen durch Simulation
2008
Kohler, T.
Über die Klassifizierung akustischer Interventionssequenzen bei essentieller
Hypertonie
2008
Qin, Z.
Re-Design des Si-IMOLA Analog Moduls
2008
113
114
Schwarzenberger, T.
Optimierung, Miniaturisierung und Inbetriebnahme einer Impedanzelektronik für
Messungen in Lab-on-Chip-Systemen
2008
Flurschütz, T.
Automatisierte Analyse zellbasierter Daten
2009
Demmel, F.
Optimierung und Automatisierung eines zellbasierten Messsystems für
die in-vitro Diagnostik
2009
Bachmeier, M.
Entwicklung einer Präzisionsmotorsteuerung zur Atemmustersimulation
2009
Zimmermann, B.
Aktivitätsmonitor - Entwicklung und Erweiterung der Firm- und Hardware
2009
Türmer, C.S.
Konzeptionierung eines Aktivitätsmonitoring-Systems für medizinische Applikationen mit dem 3D-Accelerometer der Sendsor GmbH
2009
Zhang, L.
Erstellung einer Java Applikation eines BlackBerry Client für das Projekt COMES
2010
Zhang, X.
Finite Elemente Modellierung von Diffusion, Reaktion und Strömung im Mikrovolumen im Hinblick auf Zellmetabolismus
2010
Abele, L.
Validierung eines Systems zur Früherkennung von Lungeninfekten
bei COPD-Patienten
2010
Karrer, S.
Intelligente Implantate - Optimierung von Energieversorgung und -verbrauch
2010
Bähr, C.J.V.
Hard- und Softwareintegration für biohybride Sensorsysteme
2010
Dollinger, F.
Simulation, Entwicklung und Aufbau eines intelligenten Zellkultursystems
2010
Weiß, R.
Design, validation, and application of a practical, low cost impedance testing system for quality control of microelectrode arrays and cell layer impedance monitoring
2010
Pfister, C.
Elektro-chemische vs. opto-chemische Mikrosensor-Technologien in zellbasierten
Assays: Konstruktion eines Experimentalplatzes und Durchführung eines korrelativen Tests
2010
Röschke, K.
Evaluierung und Realisierung von haptischen und audiovisuellen Biofeedbackkomponenten
2010
Wagner, J.
Erstellung eines Feedback Management Systems
2010
Berraies, M.A.
Gedruckte Elektronik: Leiterbahnen und Sensoren auf flexiblen Substraten
2011
Jantsch, J.
Entwicklung eines modularen Leuchtensystems zur therapierelevanten Praxisraumbeleuchtung
2011
Yong, K.
Steuerkomponentenintegration in ein hochparalleles Neurochip-System
2011
Wirths, W.
Zellbasierter cometabolischer in-vitro-Sensor für Wirkstoff- und Toxizitätstests
2011
Sifferlinger, A.
Aufbau und Charakterisierung eines implantierbaren Gelöstsauerstoffsensors
2011
Wang, P.
Chemosensitivity Screening of Human Tumour Slices Treated with
Chemotherapeutical Drugs
2011
Kneitz, J.
Evaluation des telemedizinischen Assistenzsystems COMES® im klinischen und
niedergelassenen Umfeld
2011
Holzhauser, S.
Digitale Signalverarbeitung im Kontext elektrophysiologischer Messungen
2011
Kertes, K.
Inductive power transmission system für medical implants
2012
Hinderer, K.-U.
Entwicklung eines telemedizinischen Bewegungstrainers als Home Care Produkt
2012
Damwerth, R.
Simulation of new coil shapes for magnetic stimulation
2002
Ingerl, D.
Erprobung neuartiger Liquid-Handling Verfahren für sensitive Messungen zellulärer
Stoffwechselraten
2002
Hyca, M.
Further Development of Interdigitated Electrode Structures on Silicon Substrates for
Measurement of Cell Adhesion
2002
Muggenthaler, H.
Amperometric oxygen sensors on silicon and glass chps for the determination of
cellular respiration: calibration and evaluation
2002
Rank, D.
Simulating The Electromagneitc Excitability of Human Nerve Fibers
2006
Sahin, M.
Datenmanagement von telemedizinischen Systemen
2006
Master theses
115
116
Riecke, C.
Design of an Oxygenation Box for Pancreas Preservation by the Two-Layer Method
before Islet Isolation
2006
Trexler, M.
Trial of a therapeutic acoustic feedback system
2007
Beck, A.
Treatment of hypertension with music - effects on human brain and body
2007
Vanoni, C.
Redesign of a Wireless voltmeter for use in clinical enviroment
2007
Nicoletti
Magnetic stimulation of organotypic neuronal cell cultures on multielectrode arrays
2007
He, Fan
Development of Battery Management System for EFOY Fuel Cell Family
2007
Nkwetchou, A.
Production and characterisation of Iridium oxide layers for biomedical pH sensors
2008
Georg, C.
Evaluation of bioaccousticly effective sound patterns to influence metabolic and
central nervous functions
2008
Janzen, N. H.
Etablierung und Standardisierung eines zellulären Testsystems für den Einsatz im
Intelligent Microplate Reader
2008
Maroun, D.
Technische Erprobung und Optimierung eines bioakustischen therapeutischen
Feedbacksystems
2008
He, Bin
Entwicklung eines Algorithmus zur Atemmustererzeugung bei Ein- und Ausatemvorgängen
2008
Mao, G.
Optimization and Validation of lung function testing
2009
Seitz, A.
Conceptual Design, Component Evaluation and Prototype Construction of a Digital
3D Surgical Microscope
2009
Hu, B.
Experimentelle und theoretische Untersuchung eines Konzeptes für
selbst-kalibrierende Sauerstoff-Mikrosensoren
2009
Hong, Y:
Oligogalacturonic acids and the interactions between enteropathogenic bacteria
and intestinal cells: Study using a novel sensor microsystem
2009
Zhang, H.
Aufbau und Evaluierung einer Medikamentendosiervorrichtung
auf Mikropumpenbasis
2010
Hao, X.
Entwicklung einer Auswertungssoftware und Datenschnittstelle für ein
hochparalleles Neurochipsystem
2010
Rekovets, K.
Automatische Erkennung von Schlafbezogenen Atemstörungen
2010
Mühlfeld, J.
Mikrocontrollersysteme und Datenübertragungsschnittstellen bei intelligenten
Implantaten
2010
Xu, T.
Development and evaluation of pump systems for drug delivery systems
2011
Liu, Z.
Optimization of a culture medium for the analysis of tumour tissue slices in high
content screening systems
2011
Handwerker, M.
Evaluation, Integration und Test eines geeigneten Data Mining Algorithmus für
COMES® auf Android-Basis
2011
Häcker, M.
Entwicklung eines elektronischen Morphometers zur Klassifizierung von
elektronenmikroskopischen Aufnahmen
2011
Bali, C.
Materialcharakterisierung und mehrlagiger Schaltungsaufbau für medizinische
Anwendungen
2011
Gleich, B.
Impedanzspektroskopie
2002
Grubinger, H.
ITO-Modelle
2002
Lackner, R.
Entwicklung und Konstruktion eines Gleichfeldmagneten
2002
Oberauer, A.
Optimierung eines Gleichfeldmagneten anhand numerischer Feldrechnung
2002
Erlen/Harrer
Kraftphänomene in magnetischen Wanderfeldern
2003
Gallmetzer, G.
Entwicklung einer Bluetooth-gestützten Universalschnittstelle für telemedizinische
Anwendungen
2003
Kandzia, F.
Entwicklung eines rückspülbaren Filters für Wasserqualitätssensoren
2003
Colen, S.
Entwicklung einer Placebo-Spule zur magnetischen Neurostimulation
2003
Bachelor theses
117
118
Clauss, J.
Mobiltelefone in der Telemedizin
2003
Meyer, J.
Miniaturspule für die Magnetstimulation
2004
Richter, M.
Aufbau und Inbetriebnahme eines biohybriden Monitors für Regenwasserqualität
2004
Probst, A.
Entwicklung eines Bluetooth-gestützten Hostsystems für
etelemedizinische Sensoren
2004
Rwebugisa, W.
Multiparametrische Messungen an Zellkulturen auf Sensorchips
2004
Stengel, T.
Aufbau eines Elektronenstrahlverdampfers zur Herstellung von Tantal-Sensoren
2004
v. Stein, A. M.
TPHM-Systeme zur Überwachung der Herzschlagfrequenz
2004
Gheorghe, C.
Drahtlose Herzrhythmusübertragung an ein Mobiltelefon
2004
Sommavilla, M
Entwicklung einer Messschaltung für einen multiparametrischen, bioelektronischen
Sensorchip
2004
Tröbersberger, M.
Entwicklung, Bau und Erprobung einer Stimulationseinrichtung für
in-vivo-Experimente
2004
Karg, M.
Magnetische Mikrostimulation
2004
Hörnler, B.
Entwicklung eines Bluetooth-gestützten Spirometers
2004
Stecher, M.
Entwicklung und elektrisches Design eines tragbaren Remission-Photometers
2004
Bischof, H.
Bestimmung von Bakterienkonzentrationen auf Basis des Sedimentationsverfahrens
mit passiven Sensoren
2004
Ilchmann, F.
Multielektrodenarray
2005
Ketzer, S.
Entwicklung eines elektronischen Interfaces zur Verarbeitung von
Ultraschall-Triggersignalen
2005
Dill, D.
Evaluierung der O2- und Temperatursensoren auf Glas-Sensorchips
2005
Fakhr, O.
A Study for transcutaneous Glucose Measurement
2005
Mayer, S.
Betrachtung von magnetischen Nanopartikeln in Aerosolapplikationen
2005
Grundl, D.
Entwicklung einr Langzeitspannungsversorgung und eines Softwaremoduls für das
IMOLA
2005
Kupec, J.
Iridiumoxid-pH-Sensoren
2005
Benning, D.
Development of a biochip-heating devide
2006
Mucha, A.
Untersuchungen zur Einsetzbarkeit von zellmodulierten Impedanzmessungen als
Detektionsstufe für Chromatographieverfahren
2006
Ghouil, Ouafa Ben
Electronic detection of proteins
2006
Heindlmaier, M.
Entwicklung einer optischen Datenübertragungsstrecke für die Konfiguraion einer
intelligenten Zahnschiene
2006
Huang, M.
Multiparametric Analysis of Tumour Cells under Normoxic and Hypoxic Conditions
2007
Kirchberger, A.
Telemetrisches Diagnose- und Therapiesystem für Schlafstörungen: Entwicklung
eines Sensor-Konzepts zur Bruxismusdiagnose
2007
Hofsöy, D. A.
Research and Development of an Intra-Splint Anti-Snoring Device
2007
Wartenburg, S.
Entwicklung einer Dateninterpretations-Software für den IMR
2007
Hoke, I.
Entwurf eines analogen Vorverstärkers für Multielektroden Arrays
2007
Karl, R.
Weiterentwicklung des NeuroLabs zur Durchführung multiparametrischer Messungen an elektrisch aktiven Zellen
2008
Haßler, S.
Energieoptimierte, bidirektionale Kommunikationsschnittstelle für Implantate
2008
Bachmeier, M.
Entwicklung einer digitalen Regelelektronik zur Gasmassendurchflussmessung
2008
Oberbichler, F.
Entwicklung eines intelligenten Vielkanal-Analog / Digital Wandlers zur Signalanalyse
elektrisch aktiver Zellen
2008
Brem, R.
Simulation und Entwicklung von Schaltungskomponenten für die Point-of-CareDiagnostik
2008
119
120
Stettner, F.
Entwicklung eines Energiekonzeptes für den Intelligent Microplate Reader (IMR) und
Miniaturisierung der Elektronikkomponenten
2008
Yang, L.
Finite Elemente Simulation der Termperaturverhältnisse in einem high-contentscreening System
2008
Wirths, W.
Optimierung des IrOx Sensors für die pH-Wert Messung
2008
Karrer, S.
Energieoptimiertes Sensorkonzept zur Messung von statischen Kieferkräften
2008
Dollinger, F.
Visualisierung der Messdaten am Intelligent Microplate Reader
2008
Issa, R.
Vermessung physiologischer Zusammenhänge an lebenden Zellen auf Basis des
NeuroLabs
2009
Mzoughi, N.
Evaluierung biokompatibler halbleitender Polymerschichten für die Herstellung
bioelektrischer Sensoren mittels Inkjet-Verfahren
2009
Strasser, S.
Entwicklung eines Pneumotachographen zur Früherkennung von Exazerbationen
2009
Havla, L.
Entwicklung eines miniaturisierten Vorverstärker- und Filterdesigns für
Aktionspotentialmessungen an elektrisch aktiven Zellen
2009
Gall, M.
Entwicklung eines 24-fach Zellkulturkammersystems für hochintegrierte NeuroChips
2009
Jansch, J.
Betrachtungen zur Funktionalität von NeuroLab und NeuroPlate im Vergleich zum
Stand der Forschung und Technik
2009
Zhang, X.
Finite Elemente Modellierung zur Sensor-Detektion zellmetabolischer Aktivität
2009
Krämer, M.
Vorbereitung von nicht-adhärenten Zellen und Gewebeschnitten für Aktivitätsmessungen mit einem Zellchip Messsystem
2009
Fleischer, K.-H.
Entwurf und Optimierung eines variabel einsetzbaren Parallelverstärkers zur Signalaufbereitung von in-vitro gemessenen Aktionspotenialen
2010
Kertes, M.
Development of an inductive power transmission system for medical implants and
devices
2010
Hollauer, M.
IMREM - Ein Hardware Emulator für das IMR-System
2010
Novitzki, M.
Entwicklung und Erprobung eines interaktiven Tools zum Audiotherapiemanagement
2010
Herber, C.
Miniaturisierung eines Systems zum Monitoring von Schnarchen und OSA
2010
Ortiz Rojas, J.C.
Entwicklung und Validierung eines Lungenfunktionssimulators
2010
Stadler, F.
Re-Design des IMOLA-S Analogmoduls
2010
Gepperth, J.
Entwurf eines Demonstrators zur Evaluierung laserstrukturierter Planarsensoren
2010
Hildbrand, C.
Entwicklung und Evaluierung von Medikamentendosierungseinheiten mit
thermischer Aktorik
2010
Pauer, M.J.
Entwicklung eines telemedizinischen Pedaltrainers
2011
Messaoud, S.
Validation study of a finite element model for reaction and diffusion using
electro-chemical and mathematical methods
2011
Eisler, J.
Intelligentes Implantat zum Tumour-Monitoring: Aufbau eines biokompatiblen
Packaging für das IntelliTuM-Projekt
2011
Listl, A.
Entwicklung eines tetrapolaren Impedanzmesssystems für die zelluläre in-vitro
Diagnostik durch Impedanzspektroskopie auf einem Biochip
2011
Dörr, L.
Integration einer Impedanzmessung in ein nichtinvasives Medizinprodukt
2011
Eichinger, A.
Konzeption und Realisierung einer GSM-Funkübertragungseinheit - Zulassung als
Medizinprodukt
2011
Polder, B.
Charakterisierung von On-Chip Referenzelektroden
2011
Scheid, E.
Entwurf und Fertigstellung eines Funkdongles für ein handelsübliches
Fieberthermometer
2011
Haid, P.
Optimierung eines telemedizinischen Assistenzsystems zur Durchführung von
klinischen Untersuchungen
2011
Kertes, K.
Untersuchung der Effekte auf Zellmetabolismus und Zellmorphologie durch
Blockieren von Na+/H+-Antiportern der Zellmembran durch Messungen mit einem
neuen, Sensor-basierten Testsystem
2011
121
Schmelzer, P.
Entwicklung eines komfortablen Stirnbands für ein Langzeitmanagement schlafbezogener Atemstörungen
2011
Bachinger, T.
Entwicklung eines auf Iridiumoxid basierenden, miniaturisierten pH-Messgeräts
2011
Polterauer, D.
Evaluierung und Optimierung einer Biofeedbackmethode mittels Vibrationen von
positionellen, schlafbezogenen Atemstörungen
2011
Hinderer, K.-U.
Charakterisierung von selbst-kalibrierenden Sauerstoff-Sensoren auf Keramikbasis
2011
Anschütz, L.
Entwicklung einer Versuchsplattform zum Auslesen von opto-chemischen Sensoren
für zellbasierte Assays
2012
Vogl, J.
Entwicklung einer automatischen Datenausgabe via Bluetooth zu einem
Mobiltelefon
2012
Kotyczka, P.
PD-Regler für Hochspannung Magnetstimulator
2003
Bauer, A.
Optimierung und Kontaktierung von Sensorsystemen für die Verwendung
von Multiwellplatten
2004
Rothenwallner, K.
Entwicklung eines Wassermonitoring-Systems mit digitaler Sensorregelung
2004
v. Gorkom, D.
Entwicklung einer Microcontroller-Testschaltung
2004
Djermester, A.
Entwicklung eines Bluetooth™ gestützten Inhalationsdatenerfassungsgeräts
2004
Sellmeir, M.
Programmierung der Auswertesoftware für eine 24xMultiwellplatte
2004
Beckler, M.
Aufbau von Drucksteuerung und Messeinheit für ein automatisiertes
Patch-Clamp Setup
2004
Saffari, Sascha
Standardisierung der multiparametrischen Messungen an Zellkulturen auf
Sensorchips am TUM-screen
2005
Streibl, S.
Entwicklung einer mikrocontrollerbasierten Emulation bioelektronischer Sensorchips
zur Überprüfung von Messschaltungen
2005
Term papers
122
Becker, S.
Entwicklung und Evaluierung eines mobilen Medizinproduktes zur Mesusng von
Lungenfunktionswerten
2005
Hebebrand, M.
Auslösen von Aktionspotentialen durch zeitlich variable Ströme - eine Simulation
2005
Veit, A.
Entwicklung einer Datenbank mit Web-Interface
2005
Schiopu, D.
PH-Sensoren auf Metalloxid-Basis - Messaufbau und Charakterisierung
2005
Füeßl, F.
Fern-Konfiguration und Wartung von mobilen Endgeräten
2006
Katz, S.
Development of a CNT-based sensor for measurements of dissolved oxygen in
fluidics
2006
Stecher, R.
Tragbares Remissions-Photometer
2006
Gharbi, A.
Telemetrisches Diagnose- und Therapie-System für Schlafstörungen
2006
Gül, M.
Entwicklung eines Sensormultiplexers zur Statusüberwachung eines
Zellchip-Messsystems
2006
Schwarzenberger, T.
Elektrochemische Deposition von Iridiumoxid auf Platinelektroden und deren
Charakterisierung als biomedizinische pH-Sensoren
2006
Dahmani, C.
Erstellung einer Controllerschaltung in RoHS-konformer SMD-Technologie
2006
Baumann, D.
Entwicklung eines Software-gestützten Analysetools für komplexe akustische
Signale
2006
Beidenhauser, G.
Entwicklung einer bidirektionelen RF-Schnittstelle für medizinische Implantate
2006
Federsel, T.
Entwicklung und Realisierung einer Teststrategie für ein aktives Medizingerät
2007
Lassoued, N.
Regelung des CO2-Gasgehaltes in miniaturisierten Zellkultur-Inkubatoren
2007
Bähr, J.
Entwicklung einer drahtlosen Weitstreckenübertragung mit Internetanbindung für
mobile Messgeräte
2007
Fu, W.
Mobile Feedbackplattform für personalisierte, medizinische Sensoren
2007
Turki, Y.
Durchführung von Gerätetests am IMR zur Unterstützung der Integrationsphase
2007
123
124
Hu, M.
Theoretische und experimentelle Untersuchungen zur Ionenwanderung, induziert
durch dynamische Magnetfelder
2007
Flurschütz, T.
Evaluierung von Analysemethoden für musikalische Signale
2007
Kiermaier, J.
Entwicklung eines mobilen Belastungsmonitors
2008
Seidl, D.
Designstudie zur Miniaturisierung einer Mixed-Signal-Elektronik in einem
biomedizinischen Handheld Device
2008
Sellami, M. A.
Einfluss der Amplitude und weiterer Messparameter auf die Impedanzmessung an
Zellkulturen
2008
Helling, F.
Konstruktion von Versuchsaufbauten für magnetstimulatorische Untersuchungen
2008
Schneider, C.
Evaluierung überoptimaler Musiksequenzen im Rahmen einer Biofeedbacktherapie
bei essentieller Hypertonie
2008
Jutzi, P.
Dreidimensionale CGI Simulation einer aktiven Nervenzellkultur auf
unterschiedlichen Zellsoren
2009
Luchian, C.
Entwicklung einer Servomotorsteuerung für ein High-Throughput Screening System
2009
Hong, S.
Entwicklung eines universellen Datenlogger- und Displaymoduls
2009
Yong, K.
Miniaturisierung analoger Verstärker- und Filterstrukturen für ein hochparalleles
planares Neurochip-System
2010
Sifferlinger, A.
Entwicklung einer Digitalelektronik für ein Implantat
2010
Grazek, R.
Intelligentes Implantat zum Tumour-Monitoring
2010
Weiß, R.
Erprobung neuartiger Herstellungverfahren biokompatibler Sensorchips
2010
Holzhauser, S.
Auslegung, Aufbau und Analyse eines Sensorsystems für ein Laborgerät
2010
Götz, P.
Entwicklung eines elektischen Messsystems zum Auslesen von optochemischen
Sensoren für pH und Gelöstsauerstoff
2010
Rieder, A.
Herstellung von koaxialen amperometrischen Sauerstoff-Mikrosensoren
2011
Haug, V.
Anwendung und Evaluierung eines Prüfprotokolls zur Messung der Zytotoxizität
mithilfe der multiparametrischen Messplattform „IMR-System“
2012
Bozsak, C.
Auswirkungen eines hydrodynamischen Scherfeldes auf die Kontur adhärenter
Zellen in Mikroreaktionskammern
2012
125
Impressum
Editor
Prof. Dr. Bernhard Wolf
Heinz Nixdorf-Lehrstuhl für Medizinische Elektronik
Theresienstrasse 90/ Geb. N3
80333 München
Tel: 089-289-22948
Fax: 089-289-22950
Website: www.lme.ei.tum.de
Editorial office / Conception
M.A. Karolin Herzog
127

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